Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs)

Danese, Alberto; Marchi, Saverio; Vitto, Veronica Angela Maria; Modesti, Lorenzo; Leo, Sara; Wieckowski, Mariusz R.; Giorgi, Carlotta; Pinton, Paolo

doi:10.1007/112_2020_43

Alberto Danese¹²,
阿尔贝托·达内塞,
Saverio Marchi¹³,
萨维里奥·马尔基,
Veronica Angela Maria Vitto¹²,
维罗妮卡·安吉拉·玛丽亚·维托，
Lorenzo Modesti¹²,
洛伦佐·莫德斯蒂
Sara Leo¹², 莎拉·里奥
Mariusz R. Wieckowski¹⁴,
马里乌斯·R·维科夫斯基，
Carlotta Giorgi¹² &
卡洛塔·乔治&
…
Paolo Pinton¹²
保罗·平顿

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 185))
系列丛书的一部分：生理学、生物化学和药理学评论（（评论，第 185 卷））

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Abstract 抽象的

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca²⁺) signals, this particular interaction controls several Ca²⁺-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca²⁺ overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca²⁺ signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca²⁺ crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.
内质网 (ER) 线粒体区域是专门的子域，也称为线粒体相关膜 (MAM)。 MAM 可以调节脂质合成，并代表离子和代谢物信号传导的中心。由于这两个细胞器可以调节钙 (Ca ²⁺ ) 信号的幅度和时空模式，因此这种特殊的相互作用控制着数条 Ca ²⁺依赖性途径，这些途径因其对肿瘤发生的贡献而闻名，例如代谢、存活、细胞敏感性死亡、转移。线粒体介导的细胞凋亡由线粒体 Ca ²⁺超载、线粒体外膜的透化以及线粒体凋亡因子释放到细胞质中引起。由于细胞凋亡依赖性细胞死亡失败是癌细胞的主要特征之一，因此正在深入研究 ER-线粒体界面处 Ca ²⁺信号传导的减少。然而，最近的一些论文将 MAM Ca ²⁺串扰相关的上调与肿瘤的发生和进展联系起来，引起了科学界的兴趣。

In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca²⁺-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca²⁺ signaling.
在这篇综述中，我们将描述不同的 MAM 定位蛋白如何通过引起 ER-线粒体相互作用的增加和减少，特别是通过调节 Ca ²⁺信号传导来调节 Ca ²⁺依赖性细胞凋亡刺激的有效性。

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Relevance of the endoplasmic reticulum-mitochondria axis in cancer diagnosis and therapy
内质网-线粒体轴在癌症诊断和治疗中的相关性

Article Open access 文章开放获取 04 January 2024 2024 年 1 月 4 日

Alterations in Ca2+ Signalling via ER-Mitochondria Contact Site Remodelling in Cancer
通过癌症中 ER-线粒体接触位点重塑改变 Ca2+ 信号转导

Emerging molecular mechanisms in chemotherapy: Ca²⁺ signaling at the mitochondria-associated endoplasmic reticulum membranes
化疗中的新兴分子机制：线粒体相关内质网膜上的 Ca ²⁺信号传导

Article Open access 文章开放获取 28 February 2018 2018 年 2 月 28 日

Keywords 关键词

1 Introduction
1简介

Ca²⁺ is the third most abundant metal in nature, and it was adopted as a regulator in the early evolutionary stages in prokaryotes (Cai et al. 2015). Ca²⁺ ions play a crucial role in countless biological processes, and one of their most important contributions is undoubtedly represented by Ca²⁺ signaling, a complex network of extra- and intracellular messenger systems that mediates a wide range of pathways (Rimessi et al. 2020). The characterization of the complex network involving Ca²⁺ signaling has been in progress for approximately 140 years since the first experiments examining the contraction of isolated rat hearts (Ringer 1883). Since then, extensive progress has been made in understanding the numerous molecular pathways involved, although many aspects are still being debated and still need to be defined. Evolutionarily, cells have developed systems to constantly maintain Ca²⁺ concentrations at very low background levels to avoid the precipitation of phosphate salts, making this ion the logical choice for the exchange of signals (Carafoli and Krebs 2016). The crucial role of Ca²⁺ in cell biology results from the ability of cells to shape Ca²⁺ signals in the dimensions of space, time, and amplitude (Alonso et al. 2009).
Ca ²⁺是自然界中第三丰富的金属，它在原核生物的早期进化阶段被用作调节剂（Cai et al. 2015 ）。 Ca ²⁺离子在无数的生物过程中发挥着至关重要的作用，其最重要的贡献之一无疑是 Ca ²⁺信号传导，这是一个介导多种途径的细胞外和细胞内信使系统的复杂网络（Rimessi 等） 2020 ）。自第一次检查离体大鼠心脏收缩的实验以来，涉及 Ca ²⁺信号传导的复杂网络的表征已经进行了大约 140 年（Ringer 1883 ）。从那时起，尽管许多方面仍在争论并且仍需要定义，但在理解所涉及的众多分子途径方面取得了广泛进展。经过进化，细胞已经开发出了能够将 Ca ²⁺浓度持续维持在极低背景水平的系统，以避免磷酸盐沉淀，从而使该离子成为信号交换的合理选择（Carafoli 和 Krebs 2016 ）。 Ca ²⁺在细胞生物学中的关键作用源于细胞在空间、时间和幅度维度上形成 Ca ²⁺信号的能力（Alonso et al. 2009 ）。

Ca²⁺ enters cells through an assortment of Ca²⁺-permeable channels that respond to different stimuli or acts as a second messenger, e.g., in the phosphoinositol signaling pathway, in which inositol trisphosphate (IP3) binds to Ca²⁺ channels on the endoplasmic reticulum (ER), transporting Ca²⁺ into the cytoplasm. Once in the cell, the effects of Ca²⁺ can be mediated by direct binding to its effectors, such as the phosphatase calcineurin, or indirectly by activating the ubiquitous Ca²⁺-binding protein calmodulin, leading to the regulation of target molecules such as the Ca²⁺/calmodulin-dependent kinases CaMKII and CaMKIV (Kerkhofs et al. 2017). Temporally and spatially defined Ca²⁺ changes in the cytoplasm or in well-defined organelles represent a highly versatile intracellular signal capable of regulating many different processes, including depolarization, hormonal secretion, contraction of smooth and striated muscles, and cellular replication and activation of cytoplasmic, mitochondrial, and nuclear enzymes (Giorgi et al. 2018a).
Ca ²⁺通过各种 Ca ²⁺渗透性通道进入细胞，这些通道响应不同的刺激或充当第二信使，例如在磷酸肌醇信号传导途径中，其中肌醇三磷酸 (IP3) 与细胞上的 Ca ²⁺通道结合。内质网（ER），将Ca ²⁺转运到细胞质中。一旦进入细胞，Ca ²⁺的作用可以通过直接结合其效应物（例如磷酸酶钙调神经磷酸酶）来介导，或通过激活普遍存在的 Ca ²⁺结合蛋白钙调蛋白来间接介导，从而调节靶分子，例如Ca ²⁺ /钙调蛋白依赖性激酶 CaMKII 和 CaMKIV (Kerkhofs et al. 2017 )。细胞质或明确细胞器中的时间和空间限定的 Ca ²⁺变化代表了高度通用的细胞内信号，能够调节许多不同的过程，包括去极化、激素分泌、平滑肌和横纹肌的收缩以及细胞复制和细胞质激活、线粒体和核酶（Giorgi 等人， 2018a ）。

Proteins that participate in Ca²⁺ signaling are mostly ubiquitous, but their distribution is highly tissue-specific (Berridge et al. 2003). Cells that need rapid Ca²⁺ signals, such as myocytes, express many voltage-activated calcium channels to allow quick Ca²⁺ entry through the plasma membrane, which then, via ryanodine receptors (RyRs) on the sarcoplasmic reticulum, triggers further calcium release. However, nonexcitable cells display calcium oscillations that last for tens of seconds and preferentially use the phosphoinositol signaling pathway to control gene expression and metabolism (Cui et al. 2017).
参与Ca ²⁺信号传导的蛋白质大多普遍存在，但它们的分布具有高度的组织特异性（Berridge et al. 2003 ）。需要快速 Ca ²⁺信号的细胞（例如肌细胞）表达许多电压激活的钙通道，以允许 Ca ²⁺快速穿过质膜进入，然后通过肌浆网上的兰尼碱受体 (RyR) 触发进一步的钙释放。然而，非兴奋性细胞会表现出持续数十秒的钙振荡，并优先使用磷酸肌醇信号通路来控制基因表达和代谢（Cui et al. 2017 ）。

Therefore, a lack of Ca²⁺ ions can lead to various issues, and excess Ca²⁺ ions have harmful effects. Indeed, a sustained rise in intracellular Ca²⁺ is considered the initial step of irreversible cellular injury, mediated by the activation of the intracellular self-destructive lysosomal enzymes responsible for breakdown of subcellular organelle membranes and increases in oxidative stress and for the hyperactivation of phospholipases and endonucleases, which, through DNA damage, participate in apoptosis (Danese et al. 2017). Intracellular Ca²⁺ signals are controlled by Ca²⁺ influx through the plasma membrane (PM) and Ca²⁺ release from intracellular stores, mainly the ER and Golgi. Intracellular Ca²⁺ stores are constantly refilled while cytosolic Ca²⁺ is extruded from the cell by the plasma membrane Ca²⁺ ATPase (PMCA) pump, to maintain the optimal cytosolic Ca²⁺ concentration (Marchi et al. 2018).
因此，缺乏Ca ²⁺离子会导致各种问题，而过量的Ca ²⁺离子则会产生有害影响。事实上，细胞内 Ca ^{2+ 的}持续升高被认为是不可逆细胞损伤的第一步，由细胞内自毁性溶酶体酶的激活介导，该酶负责亚细胞细胞器膜的分解、氧化应激的增加以及磷脂酶的过度激活和核酸内切酶，它们通过 DNA 损伤参与细胞凋亡 (Danese et al. 2017 )。细胞内 Ca ²⁺信号由通过质膜 (PM) 的 Ca ²⁺流入和细胞内储存（主要是内质网和高尔基体）释放的 Ca ²⁺控制。细胞内 Ca ²⁺储存不断补充，而胞质 Ca ²⁺则通过质膜 Ca ²⁺ ATPase (PMCA) 泵从细胞中挤出，以维持最佳胞质 Ca ²⁺浓度 (Marchi et al. 2018 )。

In the cell, one of the organelles in which changes in [Ca²⁺] are particularly important is the mitochondrion (Giorgi et al. 2018b), which decodes Ca²⁺ signals in very sensitive and specific inputs that regulate metabolism, energy production, autophagy, and apoptosis (Giorgi et al. 2018a).
在细胞中，[Ca ²⁺ ] 变化特别重要的细胞器之一是线粒体（Giorgi et al. 2018b ），它以非常敏感和特定的输入方式解码 Ca ²⁺信号，调节新陈代谢、能量产生、自噬和细胞凋亡（Giorgi et al. 2018a ）。

Membrane juxtaposition of both the mitochondria and the ER leads to the highly specialized MAMs compartment, which can be defined as areas of close organelle apposition but that are biochemically distinct from pure mitochondria and pure ER (Morciano et al. 2018). These contact sites are part of abundant heterotypic contacts, which, especially in recent years, have been well characterized and which include the ER-plasma membrane, ER-Golgi, lipid droplets–peroxisomes, mitochondria-lipid droplets, mitochondria–vacuoles/endosomes/lysosomes, ER-lipid droplets, mitochondria-plasma membrane, mitochondria–peroxisomes, ER-lipid droplets, and mitochondrial inner and outer membranes (Eisenberg-Bord et al. 2016).
线粒体和内质网的膜并置导致了高度专业化的 MAM 区室，它可以被定义为紧密细胞器并置的区域，但在生化上与纯线粒体和纯内质网不同 (Morciano et al. 2018 )。这些接触位点是丰富的异型接触的一部分，特别是近年来，这些接触已得到很好的表征，包括内质网质膜、内质网高尔基体、脂滴-过氧化物酶体、线粒体-脂滴、线粒体-液泡/内体/溶酶体、ER-脂滴、线粒体-质膜、线粒体-过氧化物酶体、ER-脂滴和线粒体内膜和外膜 (Eisenberg-Bord等2016 ）。

To witness the strong tethering between the ER and mitochondria, an isolated MAM fraction contains membrane fragments of the outer mitochondrial membrane, the ER, and some plasma membrane proteins (Poston et al. 2013). Tomography analysis has revealed the morphology of these ER-mitochondria-connecting tethers (Csordas et al. 2006). The maintenance of this delicate structural juxtaposition results strategic for the regulation of a huge number of biological processes, essentially through Ca²⁺ exchange. Poston et al. reported that there are around 1,000 molecular components of the MAMs fraction (Poston et al. 2013) and their study led to an elucidation of the multiple roles played by this particular subcellular compartment. In particular, MAMs co-regulate and influence Ca²⁺ signaling/dynamics, synthesis/transport of lipids and lipid intermediates, autophagy, apoptosis, and energy metabolism.
为了见证 ER 和线粒体之间的牢固束缚，分离的 MAM 组分包含线粒体外膜、ER 和一些质膜蛋白的膜片段（Poston 等人， 2013 ）。断层扫描分析揭示了这些内质网线粒体连接链的形态（Csordas 等人， 2006 ）。这种微妙的结构并置的维持对大量生物过程的调节具有战略意义，主要是通过 Ca ²⁺交换。波斯顿等人。据报道，MAM 部分约有 1,000 种分子成分（Poston 等人， 2013 ），他们的研究阐明了这种特定亚细胞区室所发挥的多重作用。特别是，MAM 共同调节和影响 Ca ²⁺信号/动力学、脂质和脂质中间体的合成/运输、自噬、细胞凋亡和能量代谢。

Noteworthy is the fact that MAM structures are sensitive to physiological cell conditions and this reflects in a transient and highly variable MAM composition. The length of ER-mitochondria tethers is a determining factor, critical for an efficient Ca²⁺ transfer, and an ER-mitochondria physical distance modulation is a condition found in different pathophysiological situations. About that, these two organelles’ interplay is also involved in mitochondrial shape and size, and MAM-regulated mitochondrial fusion/fission process undoubtedly covers a crucial role in governing mitochondrial dynamics. Dynamin-related protein 1 (Drp1) is responsible for mitochondrial fission; following its activation, Drp1 translocates from the cytosol to the mitochondria and oligomerizes and constricts this organelle until its division is achieved. Focusing on mitochondrial fusion, mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) are responsible for the outer membrane fusion, while optic atrophy 1 (Opa1) mediates mitochondrial inner membrane fusion (Ponte et al. 2020).
值得注意的是，MAM 结构对生理细胞条件敏感，这反映在瞬态且高度可变的 MAM 组成中。 ER-线粒体系链的长度是一个决定因素，对于有效的Ca ²⁺转移至关重要，并且ER-线粒体物理距离调制是在不同病理生理情况下发现的条件。关于这一点，这两种细胞器的相互作用也涉及线粒体的形状和大小，MAM 调节的线粒体融合/裂变过程无疑在控制线粒体动力学方面发挥着至关重要的作用。动力相关蛋白 1 (Drp1) 负责线粒体裂变；激活后，Drp1 从细胞质转移到线粒体，并使该细胞器寡聚化并收缩，直至实现分裂。重点关注线粒体融合，线粒体融合蛋白 1 (Mfn1) 和线粒体融合蛋白 2 (Mfn2) 负责外膜融合，而视神经萎缩 1 (Opa1) 介导线粒体内膜融合 (Ponte et al. 2020 )。

MAMs are enriched in channels involved in calcium transfer, allowing perfect and synergistic signaling between the ER and mitochondria. Moreover, MAMs target many proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiopathological processes (Danese et al. 2017).
MAM 富含参与钙转移的通道，从而在 ER 和线粒体之间实现完美且协同的信号传导。此外，MAM 靶向许多具有致癌/抑癌功能的蛋白质，调节参与病理生理过程的细胞信号传导途径 (Danese et al. 2017 )。

As Ca²⁺ signaling-governed processes (such as energy production, metabolism, autophagy, and apoptosis) are dysregulated in cancer cells and play a key role in Ca²⁺ transfer and signaling in MAMs, the perturbation of these Ca²⁺ transport systems at the ER and the mitochondria in relation to tumor onset and progression has become a very hot topic, especially in recent times. In fact, the recent characterization of the many oncogenes and tumor suppressors residing at the MAMs has led many research groups to elucidate how these proteins mediate their functions by altering ER-mitochondrial Ca²⁺ transfer, thereby promoting or preventing cancer cell survival. Increases or decreases in calcium exchange through the MAMs interface can either exert protumorigenic effects (such as promoting metastatic transformations) or antitumorigenic effects (such as restoring sensitivity to apoptosis) in a cancer type- and cancer state-specific manner (Kerkhofs et al. 2018).
由于 Ca ²⁺信号传导控制的过程（例如能量产生、代谢、自噬和细胞凋亡）在癌细胞中失调，并且在 MAM 中的 Ca ²⁺转移和信号传导中发挥关键作用，因此这些 Ca ²⁺运输系统的扰动内质网和线粒体与肿瘤发生和进展的关系已成为一个非常热门的话题，特别是在最近。事实上，最近对 MAM 中许多癌基因和肿瘤抑制因子的表征已促使许多研究小组阐明这些蛋白质如何通过改变 ER 线粒体 Ca ²⁺转移来介导其功能，从而促进或阻止癌细胞存活。通过 MAM 界面增加或减少钙交换可以以癌症类型和癌症状态特异性的方式发挥促肿瘤作用（例如促进转移转化）或抗肿瘤作用（例如恢复对细胞凋亡的敏感性）（Kerkhofs 等人， 2018））。

The aim of this review is to clarify how the perturbation of Ca²⁺ signaling at the ER-mitochondria interface can play a double-sided role in tumor pathology and progression. Modulation of calcium signaling at the MAMs, highly dynamic signaling hubs, could therefore represent a good therapeutic strategy in the future.
本综述的目的是阐明 ER-线粒体界面 Ca ²⁺信号传导的扰动如何在肿瘤病理学和进展中发挥双面作用。因此，调节 MAM（高度动态的信号中枢）的钙信号传导可能代表着未来良好的治疗策略。

2 MAM-Localized Ca²⁺ Signaling Modulators in Cancer: Channels and Receptors
2癌症中 MAM 定位的 Ca ²⁺信号调节剂：通道和受体

Ca²⁺ signaling represents an important tool that regulates many physiological cellular events from proliferation to cell death. Given the pivotal role it plays in such events, it is understandable why, over the past decades, remodeling of its shape has been demonstrated to be involved in the onset of many pathological conditions, such as tumor progression (Monteith et al. 2012; Prevarskaya et al. 2014; Marchi et al. 2020). Proteins involved in the maintenance of Ca²⁺ homeostasis consist of pumps, exchangers, and channels and have been described as part of the Ca²⁺ signaling “toolkit” (Berridge et al. 2003).
Ca ²⁺信号传导是调节从增殖到细胞死亡的许多生理细胞事件的重要工具。鉴于它在此类事件中发挥的关键作用，可以理解为什么在过去的几十年中，其形状的重塑已被证明与许多病理状况的发生有关，例如肿瘤进展（Monteith et al. 2012 ; Prevarskaya等人， 2014 年；马尔奇等人， 2020 年）。参与维持 Ca ²⁺稳态的蛋白质由泵、交换器和通道组成，并被描述为 Ca ²⁺信号传导“工具包”的一部分（Berridge 等人， 2003 ）。

In resting conditions, the free cytosolic Ca²⁺ concentration is much lower than that in most extracellular fluids, and an ion concentration gradient is generated. Thus, when Ca²⁺-permeable ion channels in the plasma membrane are open, Ca²⁺ flux into the cell increases (Carafoli 2002). However, as already mentioned, Ca²⁺ signaling can be generated by both external and internal cellular sources.
在静息条件下，游离胞质Ca ²⁺浓度远低于大多数细胞外液中的浓度，并产生离子浓度梯度。因此，当质膜中的Ca ²⁺可渗透离子通道打开时，进入细胞的Ca ²⁺通量增加(Carafoli 2002 )。然而，正如已经提到的，Ca ²⁺信号传导可以由外部和内部细胞源产生。

In the cell, the main ion reservoir from which Ca²⁺ can be transferred is the endoplasmic reticulum. On the one hand, the ER is the primary cell Ca²⁺ store; on the other hand, the main cellular Ca²⁺ signaling translators are the mitochondria.
在细胞中，Ca ²⁺可以从中转移的主要离子库是内质网。一方面，ER是原代细胞Ca ^{2+ 的}储存；另一方面，主要的细胞Ca ²⁺信号传导转译者是线粒体。

Indeed, depletion of luminal ER Ca²⁺ levels is followed by a rapid increase in ion mitochondrial concentration. To ensure this interaction is effective, the ER and the mitochondria are juxtaposed on the MAMs at a short distance of approximately 10–25 nm (Csordas et al. 2006; Rizzuto et al. 1998; Marchi et al. 2014) in the smooth ER and at approximately 50 nm in the rough ER (Wang et al. 2015; Giacomello and Pellegrini 2016).
事实上，腔内 ER Ca ²⁺水平耗尽后，线粒体离子浓度迅速增加。为了确保这种相互作用有效，内质网和线粒体在平滑内质网中以大约 10-25 nm 的短距离并置在 MAM 上（Csordas 等人， 2006 年；Rizzuto 等人， 1998 年；Marchi 等人， 2014 年）粗内质网中的波长约为 50 nm（Wang 等人， 2015 年；Giacomello 和 Pellegrini ，2016 年）。

2.1 ER Side
2.1急诊室侧

Many ER-resident proteins involved in Ca²⁺ transfer have been found at the MAMs: the sarco-/endoplasmic reticulum Ca²⁺ ATPase (SERCA) and inositol 1,4,5-trisphosphate receptors (IP3R), among others. SERCAs are members of the P-type ATPase superfamily of primary active transporters (a large family of membrane-embedded pumps (Wang et al. 2015)) and can maintain the correct cytosolic and reticular Ca²⁺ concentrations.
在 MAM 中发现了许多参与 Ca ²⁺转移的内质网驻留蛋白：肌浆/内质网 Ca ²⁺ ATP 酶 (SERCA) 和肌醇 1,4,5-三磷酸受体 (IP3R) 等。 SERCA 是初级活性转运蛋白 P 型 ATP 酶超家族（膜嵌入泵大家族 (Wang et al. 2015 )）的成员，可以维持正确的胞质和网状 Ca ²⁺浓度。

The 110 kDa SERCA protein has 10 helix intramembrane domains involved in the interaction with two Ca²⁺ ions transferred to the ER lumen at the expense of adenosine triphosphate (ATP). The Ca²⁺ flux is coupled to the exchange of two to three protons moved to the cytoplasm (Palmgren and Nissen 2011). In addition to transmembrane domains, SERCA has three cytoplasmic regions: the nucleotide-binding domain (N), designed for ATP binding; the phosphorylation (P) domain, which hosts the amino acid residue phosphorylated by ATP; and the actuator (A) domain at the N-terminus, which controls enzyme dephosphorylation. During ATP hydrolysis, conformational changes in the protein domains occur, and as consequence, the intermembrane domains warp, enabling Ca²⁺ transport (Toyoshima et al. 2000; Moller et al. 2010).
110 kDa SERCA 蛋白具有 10 个螺旋膜内结构域，参与与转移到 ER 腔的两个 Ca ²⁺离子的相互作用，但需要消耗三磷酸腺苷 (ATP)。 Ca ²⁺通量与移动到细胞质的两到三个质子的交换耦合（Palmgren 和 Nissen 2011 ）。除了跨膜结构域外，SERCA 还具有三个细胞质区域：核苷酸结合结构域 (N)，设计用于 ATP 结合；磷酸化 (P) 结构域，包含被 ATP 磷酸化的氨基酸残基； N 末端的致动器 (A) 结构域控制酶的去磷酸化。在 ATP 水解过程中，蛋白质结构域发生构象变化，结果导致膜间结构域扭曲，从而实现 Ca ²⁺转运（Toyoshima 等人， 2000 ；Moller 等人， 2010 ）。

To date, at least 12 isoforms of SERCA (SERCA1a-b, SERCA2a-d, SERCA3a-f) have been identified in vertebrates (Lipskaia et al. 2014), each characterized by tissue and developmental specificity. This diversity is because SERCAs are encoded by three different genes located on three chromosomes (ATP2A1, ATP2A2, and ATP2A3), each generating alternative splicing variants that differ mainly in the C-terminus of the protein.
迄今为止，已在脊椎动物中鉴定出至少 12 种 SERCA 亚型（SERCA1a-b、SERCA2a-d、SERCA3a-f）（Lipskaia 等， 2014 ），每种亚型均具有组织和发育特异性。这种多样性是因为 SERCA 由位于三个染色体上的三个不同基因（ATP2A1、ATP2A2 和 ATP2A3）编码，每个基因都会产生主要在蛋白质 C 末端不同的替代剪接变体。

The diversities in the coding sequencing of these proteins do not affect the protein tertiary structures, which are highly conserved among all isoforms, but instead lead to differences in Ca²⁺ affinity. Among all these proteins, ubiquitous SERCA2b is the isoform with the highest Ca²⁺ affinity and plays a crucial role in the regulation of ER Ca²⁺ uptake and Ca²⁺ homeostasis (Vandecaetsbeek et al. 2009). All SERCA isoforms are present along the entire ER membrane and are not particularly enriched in MAMs.
这些蛋白质编码序列的多样性不会影响蛋白质三级结构，这些结构在所有异构体中高度保守，但会导致Ca ²⁺亲和力的差异。在所有这些蛋白质中，普遍存在的 SERCA2b 是 Ca ²⁺亲和力最高的亚型，在调节 ER Ca ²⁺摄取和 Ca ²⁺稳态中发挥着至关重要的作用 (Vandecaetsbeek et al. 2009 )。所有 SERCA 亚型都存在于整个 ER 膜上，并且在 MAM 中并不是特别富集。

SERCA activity can be modulated by many proteins. Among them, the recently identified ER-luminal protein disulfide isomerase thioredoxin-related transmembrane protein 1 (TMX1) displays palmitoylation-dependent MAMs localization. TMX1 can directly interact with SERCA2b (Gutierrez and Simmen 2018; Lynes et al. 2012) and inhibit its activity, reducing Ca²⁺ transfer.
SERCA 活性可以通过许多蛋白质调节。其中，最近鉴定的内质网管腔蛋白二硫键异构酶硫氧还蛋白相关跨膜蛋白1（TMX1）显示出棕榈酰化依赖性MAMs定位。 TMX1 可以直接与 SERCA2b 相互作用（Gutierrez 和 Simmen 2018 ；Lynes 等人2012 ）并抑制其活性，减少 Ca ²⁺转移。

If SERCA activity is lowered by TMX1, its activity is enhanced by the redox active form of the redox-sensitive selenoprotein N (SEPN1) (Gutierrez and Simmen 2018). MAMs result particularly enriched in redox regulatory proteins, and TMX1 and SEPN1 are among them (Krols et al. 2016; Marino et al. 2015).
如果 TMX1 降低 SERCA 活性，则氧化还原敏感硒蛋白 N (SEPN1) 的氧化还原活性形式会增强其活性 (Gutierrez 和 Simmen 2018 )。 MAM 特别富含氧化还原调节蛋白，TMX1 和 SEPN1 就是其中之一（Krols 等人， 2016 年；Marino 等人， 2015 年）。

Calnexin is a chaperone protein that localizes at the ER-mitochondrial contact sites in a palmitoylation-dependent manner (Lynes et al. 2012). The primary function of this protein is to interact with misfolded proteins to improve the folding efficiency of ER proteins (Lamriben et al. 2016). Upon palmitoylation, calnexin moves to the MAMs, where it interacts with SERCA2b, increasing Ca²⁺ transfer from the cytosol to the ER (Lynes et al. 2013). Interestingly, the modulation of SERCA2b activity by calnexin is counteracted by TMX1 in a way that may suggest competition for the same binding site (Krols et al. 2016; Raturi et al. 2016).
钙连接蛋白是一种伴侣蛋白，以棕榈酰化依赖性方式定位于内质网线粒体接触位点（Lynes et al. 2012 ）。该蛋白的主要功能是与错误折叠的蛋白相互作用，以提高 ER 蛋白的折叠效率 (Lamriben et al. 2016 )。棕榈酰化后，钙联蛋白移动到 MAM，与 SERCA2b 相互作用，增加 Ca ²⁺从细胞质到内质网的转移 (Lynes et al. 2013 )。有趣的是，钙联蛋白对 SERCA2b 活性的调节被 TMX1 抵消，这可能表明对同一结合位点的竞争（Krols 等人， 2016 年；Raturi 等人， 2016 年）。

IP3Rs are large-conductance nonselective cation channels that together with the RyRs, which is mainly expressed in sarcoplasmic reticulum, are major structures through which Ca²⁺ exits the ER (Ashby and Tepikin 2001).
IP3Rs是大电导非选择性阳离子通道，与主要在肌浆网中表达的RyRs一起，是Ca ²⁺离开内质网的主要结构(Ashby and Tepikin 2001 )。

IP3R channels are homo- or heterotetramers composed of four subunits of approximately 300 kDa each. The molecular structure of the IP3R monomer, determined by cryogenic electron microscopy, consists of three structural domains: an N-terminal ligand-binding domain, containing both the IP3-binding core and the suppressor region, a central modulatory domain, and a Ca²⁺ channel region at the C-terminus containing six intramembrane helices. The C-tails interact directly with the N-terminal domains of the other subunits (Fan et al. 2015).
IP3R 通道是由四个亚基组成的同源或异源四聚体，每个亚基约 300 kDa。通过低温电子显微镜确定的 IP3R 单体的分子结构由三个结构域组成：N 端配体结合域（包含 IP3 结合核心和抑制区域）、中央调节域和 Ca ^{2 +} C 末端的通道区域包含六个膜内螺旋。 C 尾直接与其他亚基的 N 端结构域相互作用（Fan 等人， 2015 ）。

In vertebrates, there are three different isoforms of IP3R (IP3R1, IP3R2, and IP3R3) encoded by three genes (ITPPR1, ITPR2, and ITPR3, in humans). Despite the high homology in the amino acid sequences (60–80%), these isoforms have a different expression pattern, with IP3R1 mainly expressed in neuronal cells, IP3R2 in muscle and liver cells, and ubiquitous IP3R3 in most cultured cells (Mikoshiba 2007; Foskett et al. 2007). In addition, the different isoforms show differences in ligand-binding sensitivity and regulation by Ca²⁺ and ATP (Newton et al. 1994; Miyakawa et al. 1999; Tu et al. 2005; Khan et al. 2006; Betzenhauser et al. 2008; Wagner 2nd et al. 2008; Vervloessem et al. 2015).
在脊椎动物中，IP3R 存在三种不同的亚型（IP3R1、IP3R2 和 IP3R3），由三个基因（在人类中为 ITPPR1、ITPR2 和 ITPR3）编码。尽管氨基酸序列具有高度同源性（60-80%），但这些亚型具有不同的表达模式，IP3R1主要在神经元细胞中表达，IP3R2在肌肉和肝细胞中表达，而IP3R3在大多数培养细胞中普遍存在（Mikoshiba 2007 ；福斯克特等人， 2007 年。此外，不同的亚型在配体结合敏感性以及Ca ²⁺和ATP 调节方面表现出差异（Newton 等人， 1994 年；Miyakawa 等人， 1999 年；Tu 等人， 2005 年；Khan 等人， 2006 年；Betzenhauser 等人，2006 年）。 2008 ；瓦格纳 2nd 等人， 2015 年）。

IP3Rs are enriched at MAMs levels, where they also exert a structural role, being in close proximity with the mitochondrial voltage-dependent anion channel 1 (VDAC1) and by interacting with the chaperone glucose-regulated protein GRP75 which acts as a tether between the two proteins and organelles (Bernard-Marissal et al. 2018). It has also been recently highlighted that IP3R isoforms differently regulate ER-mitochondrial contacts and local calcium transfer, proving that IP3Rs structural role in MAM compartment is crucial (Bartok et al. 2019).
IP3R 在 MAM 水平上富集，它们也发挥结构作用，与线粒体电压依赖性阴离子通道 1 (VDAC1) 紧密相连，并通过与伴侣葡萄糖调节蛋白 GRP75 相互作用，GRP75 充当两者之间的系绳蛋白质和细胞器（Bernard-Marissal 等人， 2018 ）。最近还强调，IP3R 亚型以不同方式调节 ER 线粒体接触和局部钙转移，证明 IP3R 在 MAM 区室中的结构作用至关重要 (Bartok et al. 2019 )。

The activity of IP3R receptors is regulated primarily by inositol trisphosphate (IP3), released at the plasma membrane after the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC).
IP3R 受体的活性主要受肌醇三磷酸 (IP3) 调节，在磷脂酶 C (PLC) 水解磷脂酰肌醇 4,5-二磷酸 (PIP2) 后，IP3 在质膜上释放。

However, IP3Rs can also be modulated by ATP, post-translational modification (Mak and Foskett 2015; Bansaghi et al. 2014; Yule et al. 2010; Prole and Taylor 2016; Ivanova et al. 2014; Ramos-Franco et al. 1998), and Ca²⁺ ions, which act both from the luminal ER side, increasing the sensitivity to its ligand, and from the cytoplasmatic sides from which Ca²⁺ plays a dual role as an activator at low concentrations and an inhibitor if its concentration is higher than 300 nM (Table 1).
然而，IP3R 也可以通过 ATP、翻译后修饰进行调节（Mak 和 Foskett 2015 ；Bansaghi 等人2014 ；Yule 等人2010 ；Prole 和 Taylor 2016 ；Ivanova 等人2014 ；Ramos-Franco 等人1998） ) 和 Ca ²⁺离子，它们都从管腔起作用ER 侧，增加对其配体的敏感性，并且来自细胞质侧，Ca ²⁺在低浓度下发挥双重作用，作为激活剂，如果其浓度高于300 nM，则作为抑制剂（表1 ）。

As noted earlier, there is a juxtaposition between the two MAM-forming organelles, and Ca²⁺ release from the ER is followed by uptake at the mitochondrial interface.
如前所述，两个 MAM 形成细胞器之间并置，Ca ²⁺从内质网释放后被线粒体界面吸收。

2.2 Mitochondrial Side
2.2线粒体侧

After being released from the ER, Ca²⁺ ions can first cross the outer mitochondrial membrane through VDAC and, once in the mitochondrial intramembrane space, enter the matrix through the mitochondrial Ca²⁺ uniporter (MCU).
从内质网释放后，Ca ²⁺离子首先可以通过 VDAC 穿过线粒体外膜，一旦进入线粒体膜内空间，就通过线粒体 Ca ²⁺单向转运蛋白 (MCU) 进入基质。

VDAC is a 30-kDa protein existing in all eukaryotic cells in three different isoforms: VDAC1 and VDAC2 are expressed in most mammals, and VDAC3 is the isoform with the lowest expression (De Pinto et al. 2010; Huang et al. 2014; Maldonado et al. 2013). VDAC is the most abundant outer mitochondrial membrane protein, and due to its permeability not only to anions but also to respiratory substrates, ATP, reactive oxygen species (ROS), and cytochrome C can be considered master regulators of mitochondrial bioenergetics (Shoshan-Barmatz et al. 2010; Weisthal et al. 2014). The permeability of this channel is highly impacted by its two conformational states, opened and closed, since in the closed state, the channel is permeable only to small ions but not to anionic metabolites (Shoshan-Barmatz et al. 2010; Gincel et al. 2000; Schein et al. 1976). The switch between the opened and closed states is regulated by many factors, including Bcl2 family members (Tsujimoto and Shimizu 2000), Ca²⁺ ions (Bathori et al. 2006), and voltage. Indeed, high mitochondrial voltages induce VDAC to close (Gincel et al. 2000) in a N-terminus-mediated manner (Abu-Hamad et al. 2009).
VDAC 是一种 30-kDa 的蛋白质，以三种不同的亚型存在于所有真核细胞中：VDAC1 和 VDAC2 在大多数哺乳动物中表达，VDAC3 是表达最低的亚型（De Pinto 等人， 2010 ；Huang 等人， 2014 ；Maldonado）等人， 2013 ）。 VDAC 是最丰富的线粒体外膜蛋白，由于其不仅对阴离子具有渗透性，而且对呼吸底物、ATP、活性氧 (ROS) 和细胞色素 C 也具有渗透性，因此可被认为是线粒体生物能学的主要调节因子（Shoshan-Barmatz 等）韦斯塔尔等人， 2014 年）。该通道的渗透性受到其两种构象状态（打开和关闭）的高度影响，因为在关闭状态下，该通道仅可渗透小离子，但不可渗透阴离子代谢物（Shoshan-Barmatz 等人， 2010 年；Gincel 等人，2010 年）。 2000 ；沙因等， 1976 。打开和关闭状态之间的切换受到许多因素的调节，包括Bcl2家族成员(Tsujimoto和Shimizu 2000 )、Ca ²⁺离子(Bathori et al. 2006 )和电压。事实上，高线粒体电压会诱导 VDAC 以 N 末端介导的方式关闭 (Gincel et al. 2000 ) (Abu-Hamad et al. 2009 )。

Among VDAC channels, the most frequently expressed and consequently studied isoform is VDAC1 (Messina et al. 2012), which has been shown to be targeted to the MAMs (Hajnoczky et al. 2002; Shoshan-Barmatz and Gincel 2003; Colombini 2012) and to regulate the Ca²⁺ flux through the mitochondria outer membrane (Rapizzi et al. 2002). If regulation of mitochondrial Ca²⁺ signaling is not a unique feature of VDAC1, the ability to transmit proapoptotic stimuli to the mitochondria seems to be an exclusive characteristic of this isoform (De Stefani et al. 2012).
在 VDAC 通道中，最常表达并因此被研究的亚型是 VDAC1（Messina 等人， 2012 ），它已被证明是针对 MAM（Hajnoczky 等人， 2002 ；Shoshan-Barmatz 和 Gincel ，2003 ；Colombini ，2012 ）和调节通过线粒体外膜的 Ca ²⁺通量（Rapizzi 等人， 2002 ）。如果线粒体 Ca ²⁺信号传导的调节不是 VDAC1 的独特特征，那么将促凋亡刺激传递至线粒体的能力似乎是该亚型的独有特征 (De Stefani et al. 2012 )。

To reach the mitochondrial matrix and regulate all the previously mentioned processes, Ca²⁺ entering the outer mitochondrial membrane has to permeate the inner mitochondrial membrane that, unlike the outer membrane, is not permeable to ions. The accumulation of Ca²⁺ inside the mitochondrial matrix follows an electrogenic gradient and is driven by the low Ca²⁺ affinity uniporter complex MCU. Due to the low Ca²⁺ affinity of this MCU complex, the rapid mitochondrial ion accumulation is difficult to explain without considering the presence of close contacts between the ER and the mitochondria, which create microdomains with a high Ca²⁺ concentration (Rizzuto et al. 1998).
为了到达线粒体基质并调节所有前面提到的过程，进入线粒体外膜的 Ca ²⁺必须渗透线粒体内膜，与外膜不同，线粒体内膜不可渗透离子。 Ca ²⁺在线粒体基质内的积累遵循生电梯度，并由低 Ca ²⁺亲和力单向转运蛋白复合物 MCU 驱动。由于该 MCU 复合物的 Ca ²⁺亲和力较低，如果不考虑 ER 和线粒体之间存在的紧密接触（这会产生具有高 Ca ²⁺浓度的微域），则很难解释线粒体离子的快速积累（Rizzuto 等人） 1998 ）。

MCU is a complex of approximately 480 kDa composed of the channel-forming subunits MCUa and MCUb, organized mainly in pentamers. MCUa and MCUb have opposite effects on Ca²⁺ ion transfer (allowing and inhibiting permeation, respectively), and their relative quantities in the complex regulate the Ca²⁺ transport capability of MCU itself. In addition to the channel-forming subunits, mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) and the essential MICU regulator (EMRE) are part of the uniporter complex and play a pivotal role in regulating the integrity of the complex itself (De Stefani et al. 2015; Oxenoid et al. 2016; Raffaello et al. 2013; Sancak et al. 2013). MCU complexes were enriched in MAMs, positioned more to the mitochondrial periphery, indicating high accessibility to cytoplasm-derived Ca²⁺ inputs (Marchi et al. 2017).
MCU 是大约 480 kDa 的复合体，由通道形成亚基 MCUa 和 MCUb 组成，主要以五聚体形式组织。 MCUa和MCUb对Ca ²⁺离子传输具有相反的作用（分别允许和抑制渗透），并且它们在复合物中的相对量调节MCU本身的Ca ²⁺传输能力。除了通道形成亚基外，线粒体钙摄取 1 和 2（MICU1 和 MICU2）以及必需的 MICU 调节器 (EMRE) 也是单向转运蛋白复合物的一部分，在调节复合物本身的完整性方面发挥着关键作用 (De Stefani等人， 2015 ；拉斐尔等人， 2013 ； MCU 复合物在 MAM 中富集，更靠近线粒体外围，表明细胞质来源的 Ca ²⁺输入具有较高的可及性 (Marchi et al. 2017 )。

Among the mitochondrial Ca²⁺ uptake family of regulator proteins MICU1 and MICU2, the best characterized is MICU1, which functions as a gatekeeper that can sense the Ca²⁺ levels of the intermembrane space. Indeed, at low concentrations, the gate is closed, but as soon as the Ca²⁺ levels pass the [Ca²⁺] threshold of 700 nM for MICU1-MICU2 heterodimers and 300 nM for MICU1 homodimers, the Ca²⁺-binding EF hands of MICU1 bind the ion and undergo a conformational change that opens the channel (Csordas et al. 2013; Mallilankaraman et al. 2012a; Perocchi et al. 2010; Petrungaro et al. 2015; Park et al. 2020) (Table 1).
在线粒体Ca ²⁺摄取调节蛋白MICU1 和MICU2 家族中，特征最明显的是MICU1，它充当可以感知膜间隙Ca ²⁺水平的看门人。事实上，在低浓度下，门关闭，但一旦 Ca ²⁺水平超过 MICU1-MICU2 异二聚体的 700 nM 和 MICU1 同二聚体的 300 nM [Ca ²⁺ ] 阈值，Ca ²⁺结合 EF MICU1 的手结合离子并经历打开通道的构象变化（Csordas 等人， 2013 年；Mallilankaraman 等人， 2012a ；Perocchi 等人， 2010 年；Petrungaro 等人， 2015 年；Park 等人， 2020 年）（表1 ）。

Table 1 Summary of Ca²⁺ signaling modulators founded at MAMs and implicated in cancer onset and progression
表 1 MAM 中发现的与癌症发生和进展有关的 Ca ²⁺信号调节剂总结

Full size table 全尺寸桌子

3 Decrease in ER-Mitochondria Ca²⁺ Crosstalk
3 ER-线粒体 Ca ²⁺串扰减少

3.1 Dysfunctional ER-Ca²⁺ Release
3.1 ER-Ca ²⁺释放功能失调

As described in the introductory section, in recent years, increasing evidence has shown that organelles communicate with each other through Ca²⁺ signaling. In particular, at the MAMs level, interorganellar Ca²⁺ signaling is profoundly spatiotemporally regulated. Interestingly, in the tumor setting, an alteration of Ca²⁺ signaling has been shown to affect malignant transformation and tumor progression through the control of cell death programs and metabolism (Rimessi et al. 2020; Monteith et al. 2007).
如引言部分所述，近年来，越来越多的证据表明细胞器通过 Ca ²⁺信号传导相互通信。特别是，在 MAM 水平上，细胞间 Ca ²⁺信号传导受到深刻的时空调节。有趣的是，在肿瘤环境中，Ca ²⁺信号传导的改变已被证明可以通过控制细胞死亡程序和代谢来影响恶性转化和肿瘤进展（Rimessi 等人， 2020 ；Monteith 等人， 2007 ）。

In this context, the ER not only plays a decisive role in Ca²⁺ signaling but also guarantees a control system for correct protein folding and stress sensing. Alterations in ER homeostasis, including substantial Ca²⁺ depletion, are associated with the pathophysiology of many diseases, including cancer (Mekahli et al. 2011).
在这种情况下，ER 不仅在 Ca ²⁺信号传导中发挥决定性作用，而且还保证了正确的蛋白质折叠和应激传感的控制系统。 ER稳态的改变，包括大量Ca ²⁺消耗，与包括癌症在内的许多疾病的病理生理学相关(Mekahli et al. 2011 )。

The normal Ca²⁺ exchange between the ER and the mitochondria requires adequate filling of the ER Ca²⁺ stores. Thus, decreasing the ER Ca²⁺ levels will compromise ER-mitochondrial Ca²⁺ transfer. As a consequence, changes in the ER Ca²⁺ store content affect the Ca²⁺ efflux from the ER to the mitochondria and ultimately cell survival (Ivanova et al. 2017).
ER 和线粒体之间的正常 Ca ²⁺交换需要充分填充 ER Ca ²⁺储备。因此，降低 ER Ca ²⁺水平将损害 ER 线粒体 Ca ²⁺转移。因此，内质网 Ca ²⁺储存含量的变化会影响从内质网到线粒体的 Ca ²⁺流出，并最终影响细胞存活 (Ivanova et al. 2017 )。

The maintenance of physiological low levels of mitochondrial Ca²⁺ uptake by IP3R is crucial to preserve cellular bioenergetics in normal and cancer cells by enabling the dehydrogenase activation of the tricarboxylic acid (TCA) cycle, strong ATP production and metabolic intermediates for the generation of building blocks, allowing the cells to enter the cell cycle and proliferate. In breast cancer cells but not in normal cells, Ca²⁺ release suppression mediated by the inhibition of IP3R activity caused cell death through a deregulated autophagic mechanism (Singh et al. 2017a) and mitotic disruption, as reported by Cárdenas C. et al. (2016).
IP3R 维持线粒体 Ca ²⁺摄取的生理低水平对于保护正常细胞和癌细胞中的细胞生物能至关重要，因为它能够激活三羧酸 (TCA) 循环的脱氢酶、强大的 ATP 产生和代谢中间体以产生构建阻断，使细胞进入细胞周期并增殖。据 Cárdenas C. 等人报道，在乳腺癌细胞中（而非正常细胞中），IP3R 活性抑制介导的 Ca ²⁺释放抑制通过自噬机制失调（Singh 等人， 2017a ）和有丝分裂破坏导致细胞死亡。（ 2016 ）。

Regarding type 3 IP3R, the depletion of IP3R3 or its pharmacological blocking increased the level of the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3)-II through the upregulation of autophagic protein 5 (Atg5) and ROS generation, leading to the blockage of tumor growth in a mouse model of breast cancer (Singh et al. 2017a). This finding is correlated with the high expression of IP3R3 in human malignant tissues and high concentrations of metabolites in the serum of patients (Singh et al. 2017b).
对于 3 型 IP3R，IP3R3 的消耗或其药理学阻断通过上调自噬蛋白 5 (Atg5) 和 ROS 生成增加了自噬标记物微管相关蛋白 1A/1B-轻链 3 (LC3)-II 的水平，导致乳腺癌小鼠模型中肿瘤生长受阻（Singh et al. 2017a ）。这一发现与人类恶性组织中 IP3R3 的高表达以及患者血清中代谢物的高浓度相关（Singh et al. 2017b ）。

Moreover, it has been reported that the inhibition of IP3R with caffeine, a nonspecific inhibitor of these receptors, leads to a decreased migration of glioblastoma cells and a substantially increased mean survival in a mouse glioblastoma xenograft model (Kang et al. 2010). In the Caco-2 colon cancer cell line, IP3R3 silencing, or nonspecific pharmacological inhibition by 2-APB in gastric cancer cells, induced apoptosis, while overexpression protected cells from staurosporine-induced apoptotic death (Shibao et al. 2010).
此外，据报道，用咖啡因（这些受体的非特异性抑制剂）抑制IP3R会导致小鼠胶质母细胞瘤异种移植模型中胶质母细胞瘤细胞迁移的减少和平均存活率的显着增加（Kang等人， 2010 ）。在 Caco-2 结肠癌细胞系中，IP3R3 沉默或胃癌细胞中 2-APB 的非特异性药理抑制可诱导细胞凋亡，而过表达可保护细胞免遭星形孢菌素诱导的细胞凋亡性死亡（Shibao 等人， 2010 ）。

Interestingly, various MAM-located oncosuppressors and oncogenes have been reported to interact with IP3Rs, including the oncogene protein kinase B (PKB), also known as Akt, promyelocytic leukemia protein (PML), BRCA1 associated protein 1 (BAP1), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and B-cell lymphoma 2 (Bcl-2) family proteins, modifying the Ca²⁺ release patterns and cell fate (Bononi et al. 2017; Akl and Bultynck 2013; Missiroli et al. 2017; Kuchay et al. 2017; Giorgi et al. 2010). Although the aforementioned proteins are all present at the ER-mitochondria interface, only PTEN and PML are particularly enriched on MAMs (Missiroli et al. 2016; Bononi et al. 2013).
有趣的是，据报道，多种位于 MAM 的抑癌基因和癌基因可与 IP3R 相互作用，包括癌基因蛋白激酶 B (PKB)，也称为 Akt、早幼粒细胞白血病蛋白 (PML)、BRCA1 相关蛋白 1 (BAP1)、磷酸酶和张力蛋白10 号染色体上的同源缺失 (PTEN) 和 B 细胞淋巴瘤 2 (Bcl-2) 家族蛋白，修饰 Ca ²⁺释放模式和细胞命运（Bononi 等人， 2017 年；Akl 和 Bultynck， 2013 年；Missiroli 等人， 2017 年；Kuchay 等人， 2017 年；Giorgi 等人， 2010 年）。尽管上述蛋白质都存在于 ER-线粒体界面，但只有 PTEN 和 PML 在 MAM 上特别富集（Missiroli 等人， 2016 年；Bononi 等人， 2013 年）。

Akt, as well as protein kinase C (PKC) isozymes (Pinton et al. 2004), is a key player in regulating multiple signaling pathways through calcium signaling tuning, such as cell metabolism, cell proliferation, and survival (Szado et al. 2008). Notably, in human breast cancers, the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is frequently dysregulated (Gonzalez-Angulo et al. 2011; Stemke-Hale et al. 2008).
Akt 以及蛋白激酶 C (PKC) 同工酶 (Pinton et al. 2004 ) 是通过钙信号调节调节多种信号传导途径的关键角色，例如细胞代谢、细胞增殖和存活 (Szado et al. 2008) ）。值得注意的是，在人类乳腺癌中，磷酸肌醇 3-激酶 (PI3K)/Akt/mTOR 通路经常失调（Gonzalez-Angulo 等人， 2011 ；Stemke-Hale 等人， 2008 ）。

On the ER side, IP3R Akt-mediated phosphorylation results in a decreased magnitude of Ca²⁺ release and, as a result, reduced mitochondrial Ca²⁺ uptake. Moreover, this decrease in Ca²⁺ flux protected glioblastoma cell lines from the effects of apoptotic stimuli (Szado et al. 2008).
在 ER 一侧，IP3R Akt 介导的磷酸化导致 Ca ²⁺释放量减少，从而减少线粒体 Ca ²⁺摄取。此外，Ca ²⁺流量的减少保护胶质母细胞瘤细胞系免受细胞凋亡刺激的影响(Szado et al.2008 )。

In 2012, our group demonstrated that Akt specifically phosphorylates type 3 IP3R, leading to diminished mitochondrial Ca²⁺ influx and, consequently, protecting cells from apoptosis (Marchi et al. 2012).
2012 年，我们的小组证明 Akt 特异性磷酸化 3 型 IP3R，导致线粒体 Ca ²⁺流入减少，从而保护细胞免于凋亡（Marchi 等人， 2012 ）。

PML tumor suppressor protein has been implicated in diverse cellular processes ranging from tumor suppression to defense against virus infection (Bernardi and Pandolfi 2007; Everett and Chelbi-Alix 2007; Hsu and Kao 2018; Pinton et al. 2011). An extranuclear fraction of PML has been demonstrated to be targeted to the MAMs in a p53-dependent manner (Missiroli et al. 2016) and to form a multicomplex with type 3 IP3R, the serine threonine kinase Akt and protein phosphatase 2A (PP2A) (Giorgi et al. 2010).
PML肿瘤抑制蛋白参与多种细胞过程，从肿瘤抑制到防御病毒感染（Bernardi和Pandolfi 2007 ；Everett和Chelbi-Alix 2007 ；Hsu和Kao 2018 ；Pinton等2011 ）。 PML 的核外部分已被证明以 p53 依赖性方式靶向 MAM（Missiroli 等人， 2016 ），并与 3 型 IP3R、丝氨酸苏氨酸激酶 Akt 和蛋白磷酸酶 2A (PP2A) 形成多重复合物（乔治等人， 2010 ）。

It has been shown that PML regulates the phosphorylation of IP3R by controlling the activity of Akt through the recruitment of the PP2A phosphatase at the MAMs interface. Hence, PML can coordinate Ca²⁺ mobilization into the mitochondria, which then triggers the cell death program. Conversely, in the absence of PML, PP2A does not assemble with IP3R and Akt, resulting in a higher activation of Akt (phospho-Akt). Once activated, Akt can hyperphosphorylate IP3R, thereby suppressing ER Ca²⁺ release to the mitochondria (Giorgi et al. 2011).
研究表明，PML 通过在 MAM 界面招募 PP2A 磷酸酶来控制 Akt 的活性，从而调节 IP3R 的磷酸化。因此，PML 可以协调 Ca ²⁺动员到线粒体中，然后触发细胞死亡程序。相反，在没有 PML 的情况下，PP2A 不会与 IP3R 和 Akt 组装，从而导致 Akt（磷酸化 Akt）的更高活化。一旦激活，Akt 可使 IP3R 过度磷酸化，从而抑制 ER Ca ²⁺释放至线粒体（Giorgi 等人， 2011 ）。

BAP1 is a member of the ubiquitin C-terminal hydrolase (UCH) subfamily of deubiquitylating enzymes and has tumor suppressor activity, which has been mainly correlated with its nuclear localization (Lee et al. 2014; Ismail et al. 2014). When BAP1 localizes to the ER, it binds, deubiquitylates, and stabilizes the activity of the IP3R3 channel, modulating Ca²⁺ release from the ER to the cytosol and then to the mitochondria, promoting apoptosis. In BAP1^+/− carriers, the reduced level of BAP1 resulted in a diminished IP3R3 quote with a subsequent Ca²⁺ transfer decrease from the ER to the mitochondria. This event caused a reduced propensity of BAP1^+/− cells to undergo apoptosis following DNA damage induced by asbestos or UV light (Bononi et al. 2017).
BAP1 是去泛素化酶的泛素 C 末端水解酶 (UCH) 亚家族的成员，具有肿瘤抑制活性，这主要与其核定位相关 (Lee et al. 2014 ；Ismail et al. 2014 )。当 BAP1 定位于 ER 时，它会结合、去泛素化并稳定 IP3R3 通道的活性，调节 Ca ²⁺从 ER 释放到细胞质，然后释放到线粒体，从而促进细胞凋亡。在 BAP1 ^+/-携带者中，BAP1 水平降低导致 IP3R3 引用减少，随后从 ER 到线粒体的 Ca ²⁺转移减少。这一事件导致 BAP1 ^+/-细胞在石棉或紫外线诱导 DNA 损伤后发生凋亡的可能性降低 (Bononi et al. 2017 )。

PTEN is another Ca²⁺-related tumor suppressor that has been shown to be mutated or suppressed in many tumors (Salmena et al. 2008). Bononi et al. demonstrated that a fraction of cellular PTEN is localized at the MAMs, where it interacts with IP3R3, antagonizing its Akt-mediated phosphorylation and enhancing Ca²⁺ transfer from the ER to mitochondria. In this way, it reestablishes cellular sensitivity to Ca²⁺-mediated proapoptotic stimuli. Conversely, PTEN knockdown reduced the Ca²⁺ release from the ER and decreased mitochondrial Ca²⁺ transients, thus preventing cell death activation (Bononi et al. 2013). Moreover, a novel role for PTEN has been proposed; it can compete with F-box and leucine-rich repeat protein 2 (FBXL2), an E3-ubiquitin ligase F-box protein, for binding to IP3R3 to prevent its degradation. It has been demonstrated that FBXL2 degradation of IP3R3 is enhanced in cancer cells in which PTEN expression is lowered, thereby resulting in the inhibition of apoptosis (Kuchay et al. 2017).
PTEN 是另一种 Ca ²⁺相关肿瘤抑制因子，已被证明在许多肿瘤中发生突变或抑制（Salmena 等人， 2008 ）。博诺尼等人。证明细胞 PTEN 的一部分位于 MAM，在那里它与 IP3R3 相互作用，拮抗其 Akt 介导的磷酸化并增强 Ca ²⁺从 ER 到线粒体的转移。通过这种方式，它重新建立了细胞对 Ca ²⁺介导的促凋亡刺激的敏感性。相反，PTEN 敲低减少了 ER 的 Ca ²⁺释放，并减少了线粒体 Ca ²⁺瞬变，从而防止了细胞死亡激活（Bononi 等人， 2013 ）。此外，还提出了 PTEN 的新作用；它可以与 F-box 和富含亮氨酸的重复蛋白 2 (FBXL2)（一种 E3-泛素连接酶 F-box 蛋白）竞争与 IP3R3 的结合，以防止其降解。已证明，在 PTEN 表达降低的癌细胞中，FBXL2 对 IP3R3 的降解增强，从而抑制细胞凋亡 (Kuchay et al. 2017 )。

The Bcl-2 family of anti- and proapoptotic proteins is predominantly localized to the mitochondria, ER, and MAMs, and their activities strongly reflect their intracellular localization (Morciano et al. 2018). Bcl-2 is a proto-oncogene known for its involvement in inhibition of apoptosis through its interaction with the proapoptotic proteins BCL2 associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak) (Rimessi et al. 2020). Indeed, at the ER, Bcl-2 prevents excessive Ca²⁺ flux by directly targeting all three IP3R receptor isoforms, which would lead to mitochondrial Ca²⁺ overload and opening of the permeability transition pore (mPTP) (Chen et al. 2015; Bonora et al. 2017). Dysregulation of Bcl-2 expression has been highlighted in various cancers, including hematopoietic, lung, breast, and prostate tumors (Morciano et al. 2018).
Bcl-2 家族的抗凋亡和促凋亡蛋白主要定位于线粒体、ER 和 MAM，它们的活性强烈反映了它们的细胞内定位 (Morciano et al. 2018 )。 Bcl-2 是一种原癌基因，因其与促凋亡蛋白 BCL2 相关 X 蛋白 (Bax) 和 Bcl-2 同源拮抗剂/杀伤剂 (Bak) 相互作用而参与抑制细胞凋亡 (Rimessi et al. 2020 )。事实上，在 ER 中，Bcl-2 通过直接靶向所有三种 IP3R 受体亚型来防止过度的 Ca ²⁺通量，这将导致线粒体 Ca ²⁺过载和通透性转换孔 (mPTP) 打开 (Chen et al. 2015 ;博诺拉等人， 2017 年。 Bcl-2 表达失调在多种癌症中都得到了强调，包括造血肿瘤、肺癌、乳腺癌和前列腺肿瘤 (Morciano et al. 2018 )。

Bcl-XL is another antiapoptotic member of the same family that is frequently overexpressed in many tumors, such as multiple myeloma, melanoma, glioblastoma, prostate cancer, colorectal cancer, non-small cell lung cancer, and pancreatic cancers (Trisciuoglio et al. 2017; Scherr et al. 2016; Zhang et al. 2014; Yoshimine et al. 2013). This protein is localized at the MAMs (Monaco et al. 2015), where it directly binds the IP3R channels, regulating IP3R-related Ca²⁺ release. Bcl-XL caused a strong sensitization of IP3R, promoting prosurvival Ca²⁺ oscillations (White et al. 2005).
Bcl-XL 是同一家族的另一个抗凋亡成员，在许多肿瘤中经常过表达，例如多发性骨髓瘤、黑色素瘤、胶质母细胞瘤、前列腺癌、结直肠癌、非小细胞肺癌和胰腺癌 (Trisciuoglio et al. 2017)谢尔等人， 2016 ；张等人，2013 ；该蛋白定位于 MAM（Monaco et al. 2015 ），直接结合 IP3R 通道，调节 IP3R 相关的 Ca ²⁺释放。 Bcl-XL 引起 IP3R 强烈敏化，促进促存活 Ca ²⁺振荡（White et al. 2005 ）。

Among the antiapoptotic proteins of the Bcl-2 family, myeloid cell leukemia 1 (Mcl-1) also lowers the calcium ER store content by stimulating IP3Rs outside of the MAMs, thereby increasing Ca²⁺ leakage from the ER, resulting in a decline in the basal ER Ca²⁺ levels (Eckenrode et al. 2010). In the presence of low [IP3], in Mcl-1-expressing cells, store depletion becomes more prominent, indicating that the sensitivity of IP3-dependent Ca²⁺ release is enhanced by Mcl-1. Mcl-1-mediated IP3R sensitization also contributes to low-level IP3R-mediated Ca²⁺ signaling from the ER to the mitochondria and thereby stimulates mitochondrial bioenergetics (Bittremieux et al. 2016).
在 Bcl-2 家族的抗凋亡蛋白中，骨髓细胞白血病 1 (Mcl-1) 还通过刺激 MAM 外部的 IP3R 来降低 ER 储存的钙含量，从而增加 ER 中的 Ca ²⁺渗漏，从而导致基础 ER Ca ²⁺水平（Eckenrode 等人， 2010 ）。在低 [IP3] 存在的情况下，在表达 Mcl-1 的细胞中，储备耗尽变得更加突出，表明 Mcl-1 增强了 IP3 依赖性 Ca ²⁺释放的敏感性。 Mcl-1 介导的 IP3R 敏化还有助于从 ER 到线粒体的低水平 IP3R 介导的 Ca ²⁺信号传导，从而刺激线粒体生物能（Bittremieux et al. 2016 ）。

At the MAMs, oncogenic H-Ras also affects Ca²⁺ transfer to the mitochondria to promote evasion from the apoptotic cascade (Rimessi et al. 2014). In colorectal cancer cells, oncogenic K-Ras modified the expression of IP3Rs, weakening the Ca²⁺ release from the ER to allow cells to escape Ca²⁺-mediated apoptosis (Pierro et al. 2014). Indeed, Ras-driven mitochondrial dysfunction causes metabolic and redox changes that favor tumorigenesis (Hu et al. 2012). Hence, proper maintenance of IP3R3 protein levels is crucial for preventing oncogenesis by strengthening tumor-suppressive ER-mitochondrial Ca²⁺ transfer.
在 MAM 中，致癌 H-Ras 还会影响 Ca ²⁺向线粒体的转移，以促进细胞凋亡级联的逃避 (Rimessi et al. 2014 )。在结直肠癌细胞中，致癌 K-Ras 改变了 IP3R 的表达，削弱了 ER 的 Ca ²⁺释放，使细胞能够逃避 Ca ²⁺介导的细胞凋亡 (Pierro et al. 2014 )。事实上，Ras 驱动的线粒体功能障碍会导致有利于肿瘤发生的代谢和氧化还原变化（Hu et al. 2012 ）。因此，适当维持 IP3R3 蛋白水平对于通过加强肿瘤抑制性 ER-线粒体 Ca ²⁺转移来预防肿瘤发生至关重要。

Furthermore, MAMs are a molecular platform for the regulation of many oxidoreductases. In this context, endoplasmic reticulum oxidoreductin 1-α (ERO1-α) activity is broadly investigated for its enrichment at ER-mitochondria contact sites (Anelli et al. 2012) and its high expression in different tumor types (Kakihana et al. 2012). This oxidase impacts ER-Ca²⁺ storage and IP3-dependent fluxes. During ER stress, ERO1-α oxidizes type 1 IP3R, promoting the release of Ca²⁺ from the ER (Anelli et al. 2012). Furthermore, endoplasmic reticulum resident protein 44 (ERp44) (an ER luminal chaperone protein) binds to IP3R1 and inhibits its channel activity under reducing conditions, resulting in the blockade of Ca²⁺ transfer to the mitochondria (Higo et al. 2005). Oxidation of IP3R1 by ERO1-α causes the dissociation of ERp44, thus leading to the activation of Ca²⁺ release via IP3R1 (Li et al. 2009). ERO1-α silencing has been demonstrated to profoundly affect mitochondrial Ca²⁺ uptake, likely modifying MCU activity. Thus, ERO1-α links redox and Ca²⁺ homeostasis in MAMs (Anelli et al. 2012).
此外，MAM 是调节许多氧化还原酶的分子平台。在这种情况下，内质网氧化还原素 1-α (ERO1-α) 活性因其在 ER-线粒体接触位点的富集（Anelli et al. 2012 ）及其在不同肿瘤类型中的高表达而被广泛研究（Kakihana et al. 2012 ）。该氧化酶影响 ER-Ca ²⁺储存和 IP3 依赖性通量。在内质网应激期间，ERO1-α 氧化 1 型 IP3R，促进内质网释放 Ca ²⁺ (Anelli et al. 2012 )。此外，内质网驻留蛋白 44 (ERp44)（一种 ER 腔伴侣蛋白）与 IP3R1 结合并在还原条件下抑制其通道活性，导致 Ca ²⁺转移至线粒体的阻断 (Higo et al. 2005 )。 IP3R1被ERO1-α氧化导致ERp44解离，从而导致通过IP3R1激活Ca ²⁺释放(Li et al.2009 )。 ERO1-α 沉默已被证明会深刻影响线粒体 Ca ²⁺吸收，可能会改变 MCU 活性。因此，ERO1-α 将 MAM 中的氧化还原和 Ca ²⁺稳态联系起来（Anelli 等人， 2012 ）。

Recently, the oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3), which mediates the signaling of cytokines, growth factors, and oncogenes (Yu et al. 2014), has been shown to localize only to MAMs (Su et al. 2020). At this location, it modulates ER-mitochondria Ca²⁺ release by interacting with the IP3R3 channel and promoting its degradation, resulting in greater cellular resistance to apoptotic stimuli (Avalle et al. 2019). In breast cancer cell lines, silencing STAT3 enhances the ER Ca²⁺ release and sensitivity to apoptosis following oxidative stress, correlating with increased IP3R3 levels. This evidence suggests that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its antiapoptotic functions via Ca²⁺ flux modulation.
最近，致癌转录因子信号转导子和转录激活子 3 (STAT3) 介导细胞因子、生长因子和癌基因的信号传导 (Yu et al. 2014 )，已被证明仅定位于 MAM (Su et al. 2014)。 2020 ）。在此位置，它通过与 IP3R3 通道相互作用并促进其降解来调节 ER 线粒体 Ca ²⁺释放，从而增强细胞对凋亡刺激的抵抗力 (Avalle et al. 2019 )。在乳腺癌细胞系中，沉默 STAT3 可增强 ER Ca ²⁺释放和氧化应激后对细胞凋亡的敏感性，与 IP3R3 水平升高相关。该证据表明，ER 中 STAT3 介导的 IP3R3 下调通过 Ca ²⁺通量调节对其抗凋亡功能做出了至关重要的贡献。

Together with the IP3R receptors, RyRs and SERCA are the major Ca²⁺ players in the ER (Berridge 2012). In general, RyRs regulate melanocyte and T cell proliferation (Hakamata et al. 1994; Kang et al. 2000) and astrocyte migration (Matyash et al. 2002). Ryanodine receptor type 2 (RyR2), a member of the RyR family, controls the Ca²⁺ release from the sarcoplasmic reticulum into the cytosol (Ding et al. 2017). Different studies have confirmed the association of RyR2 with several cancer types, including melanoma (Carpi et al. 2018), breast cancer (Lu et al. 2017), lymphoma (McCarthy et al. 2003), and prostate cancer (Mariot et al. 2000). Recently, it has been reported that RyR2 is downregulated in thyroid carcinoma tissues and that low expression levels of RyR2 are closely associated with poor prognosis in thyroid carcinoma patients (Xu et al. 2019).
与 IP3R 受体一起，RyR 和 SERCA 是 ER 中主要的 Ca ²⁺参与者 (Berridge 2012 )。一般来说，RyR 调节黑素细胞和 T 细胞增殖（Hakamata 等人， 1994 ；Kang 等人， 2000 ）和星形胶质细胞迁移（Matyash 等人， 2002 ）。 Ryanodine 受体 2 型 (RyR2) 是 RyR 家族的成员，控制 Ca ²⁺从肌浆网释放到细胞质中 (Ding et al. 2017 )。不同的研究已证实 RyR2 与多种癌症类型的关联，包括黑色素瘤 (Carpi et al. 2018 )、乳腺癌 (Lu et al. 2017 )、淋巴瘤 (McCarthy et al. 2003 ) 和前列腺癌 (Mariot et al. 2017)。co;2-m" aria-label="参考 2000" data-test="引用-ref" data-track-label="链接" data-track-action="参考锚点" data-track="click">最近有报道称，RyR2在甲状腺癌组织中表达下调，且RyR2的低表达水平与甲状腺癌患者的不良预后密切相关(Xu et al. 2019 )。

Over the past years, the tumor suppressor p53 has been shown to be altered in many human cancer tissues, including colon, breast, lung, brain, bladder, pancreatic, stomach, and esophageal cancer (Vogelstein et al. 2000). Some of p53 fraction is located at the MAMs, where it directly binds to the SERCA pump, changing its oxidative state and thus leading to an increased Ca²⁺ load, followed by an enhanced flux to the mitochondria. Consequently, during apoptotic stimulation, more Ca²⁺ can be released from the ER into the mitochondria, enhancing mitochondrial Ca²⁺ overload, opening of the mitochondrial mPTP, release of caspase cofactors, and ultimately induction of the intrinsic apoptosis pathway (Morciano et al. 2018). Dysregulation of p53-dependent Ca²⁺ homeostasis led to reduced ER Ca²⁺ release, resulting in a low responsiveness to apoptotic stimulation (Giorgi et al. 2015).
在过去的几年中，肿瘤抑制因子p53已被证明在许多人类癌症组织中发生改变，包括结肠癌、乳腺癌、肺癌、脑癌、膀胱癌、胰腺癌、胃癌和食道癌（Vogelstein等人， 2000 ）。 p53 部分位于 MAM 处，直接与 SERCA 泵结合，改变其氧化状态，从而导致 Ca ²⁺负载增加，随后流向线粒体的流量增加。因此，在细胞凋亡刺激过程中，更多的 Ca ²⁺可以从 ER 释放到线粒体中，增强线粒体 Ca ²⁺超载，打开线粒体 mPTP，释放 caspase 辅因子，并最终诱导内在细胞凋亡途径 (Morciano 等人) 2018 ）。 p53 依赖性 Ca ²⁺稳态的失调导致 ER Ca ²⁺释放减少，导致对细胞凋亡刺激的反应性较低 (Giorgi et al. 2015 )。

We must also note the phosphofurin acid cluster sorting 2 protein (PACS-2) and PKR-like ER kinase (PERK). PACS-2 is a multifunctional protein involved in retrograde ER-Golgi trafficking of multiple proteins (Youker et al. 2009). Although it is unclear whether a direct interaction of PACS-2 at the MAMs occurs, it was demonstrated that depletion of PACS-2 reduces mitochondrial-ER contact sites and mediates apoptosis (Simmen et al. 2005). PACS-2 was also demonstrated to be a fundamental player in rapamycin complex 2 (mTORC2)-dependent regulation of MAMs integrity (Betz et al. 2013). PERK is a protein kinase that, together with inositol-requiring enzyme 1 (IRE1) and transcription factor 6 (ATF6), acts as an ER stress sensor from the ER membrane, controlling UPR functioning. The function of this protein in the MAMs is independent of its role as an ER stress sensor and transcriptional regulator of redox homeostasis. Indeed, PERK maintains, through its cytoplasmic domains, the juxtaposition of the ER and the mitochondria, acting as a structural tether and permitting the transmission of ROS-mediated signals (Verfaillie et al. 2012).
我们还必须注意磷酸呋喃酸簇分选 2 蛋白 (PACS-2) 和 PKR 样 ER 激酶 (PERK)。 PACS-2 是一种多功能蛋白，参与多种蛋白的逆行 ER-高尔基体运输（Youker et al. 2009 ）。尽管尚不清楚 PACS-2 在 MAM 上是否发生直接相互作用，但已证明 PACS-2 的耗尽会减少线粒体 - ER 接触位点并介导细胞凋亡（Simmen 等人， 2005 ）。 PACS-2 还被证明是雷帕霉素复合物 2 (mTORC2) 依赖性 MAM 完整性调节的重要参与者 (Betz et al. 2013 )。 PERK 是一种蛋白激酶，与肌醇需求酶 1 (IRE1) 和转录因子 6 (ATF6) 一起充当 ER 膜的 ER 应激传感器，控制 UPR 功能。该蛋白在 MAM 中的功能与其作为 ER 应激传感器和氧化还原稳态转录调节因子的作用无关。事实上，PERK 通过其细胞质结构域维持 ER 和线粒体的并置，充当结构系链并允许 ROS 介导的信号传输（Verfaillie 等人， 2012 ）。

In conclusion, changes in the ER Ca²⁺-store content would perturb Ca²⁺ transfer from the ER to the mitochondria and ultimately influence cell death or survival. A reduction in intracellular store Ca²⁺ release is certainly the main mechanism adopted by cancer cells to escape mitochondria-mediated apoptosis (Fig. 1).
总之，内质网 Ca ²⁺储存量的变化会干扰 Ca ²⁺从内质网到线粒体的转移，并最终影响细胞死亡或存活。细胞内储存Ca ²⁺释放的减少无疑是癌细胞逃避线粒体介导的细胞凋亡的主要机制（图1 ）。

3.2 Perturbed Mitochondrial Ca²⁺ Uptake
3.2线粒体 Ca ²⁺摄取受到干扰

Cancer-derived modifications in cellular physiology could be related to impairment of the Ca²⁺ signaling network, which is frequently associated with the dysregulation of several Ca²⁺ channels and pumps (Prevarskaya et al. 2014; Hanahan and Weinberg 2000).
细胞生理学中癌症衍生的改变可能与 Ca ²⁺信号网络的损伤有关，而 Ca 2+ 信号网络的损伤通常与多个 Ca ²⁺通道和泵的失调有关（Prevarskaya 等人， 2014 ；Hanahan 和 Weinberg ，2000 ）。

In addition to limiting the excessive release of Ca²⁺ from the ER, cancer cells can effectively prevent mitochondrial Ca²⁺ overload by limiting mitochondrial Ca²⁺ uptake.
除了限制内质网过度释放Ca ²⁺外，癌细胞还可以通过限制线粒体Ca ²⁺摄取来有效防止线粒体Ca ²⁺过载。

Among the proteins responsible for limitation of mitochondrial calcium influx are Bcl-2 and Bcl-XL, the antiapoptotic Bcl-2-family proteins discussed in the previous paragraph; Bcl-2 and Bcl-XL are partially localized at the mitochondrial outer membrane and, similar to other antiapoptotic proteins, are frequently upregulated in cancer; these proteins can regulate mitochondrial Ca²⁺ uptake through VDAC1 (Shoshan-Barmatz et al. 2010).
负责限制线粒体钙流入的蛋白质包括 Bcl-2 和 Bcl-XL，它们是上一段讨论的抗凋亡 Bcl-2 家族蛋白质； Bcl-2 和 Bcl-XL 部分位于线粒体外膜，与其他抗凋亡蛋白类似，在癌症中经常上调；这些蛋白质可以通过 VDAC1 调节线粒体 Ca ²⁺摄取 (Shoshan-Barmatz et al. 2010 )。

Considering that VDAC1 is involved in death and cell survival, it is not surprising that this channel could be a target for Bcl-2 family proteins (De Stefani et al. 2012). These proteins target the N-terminal region of VDAC1 (Abu-Hamad et al. 2009; Arbel and Shoshan-Barmatz 2010), and it has been demonstrated that only the Bcl-XL BH4 domain is essential to bind VDAC1 and inhibit cell death (Monaco et al. 2015). Several studies demonstrated that the interaction between Bcl-XL and VDAC1 suppresses proapoptotic Ca²⁺ uptake, preventing the dissipation of the mitochondrial potential and the release of cytochrome c and apoptosis-inducing factor (AIF) through the outer membrane.
考虑到 VDAC1 参与细胞死亡和存活，因此该通道可能成为 Bcl-2 家族蛋白的靶标也就不足为奇了 (De Stefani et al. 2012 )。这些蛋白靶向 VDAC1 的 N 末端区域（Abu-Hamad 等， 2009 ；Arbel 和 Shoshan-Barmatz ，2010 ），并且已证明，只有 Bcl-XL BH4 结构域对于结合 VDAC1 和抑制细胞死亡至关重要（摩纳哥等， 2015 ）。多项研究表明，Bcl-XL 和 VDAC1 之间的相互作用可抑制促凋亡 Ca ²⁺摄取，从而防止线粒体电位的耗散以及细胞色素 c 和凋亡诱导因子 (AIF) 通过外膜的释放。

Indeed, studies concerning mitochondrial Ca²⁺ uptake that compare Bcl-XL-overexpressing versus Bcl-XL-deficient cells have demonstrated that this protein may be involved in MAMs microdomain reorganization and results in an alteration of the capacity of mitochondrial Ca²⁺ uptake, proving that Bcl-XL inhibits VDAC1 (Monaco et al. 2015; Bittremieux et al. 2016; Shimizu et al. 2000; Li et al. 2008).
事实上，有关线粒体 Ca ²⁺摄取的研究比较了 Bcl-XL 过表达细胞与 Bcl-XL 缺陷细胞，结果表明该蛋白可能参与 MAM 微域重组并导致线粒体 Ca ²⁺摄取能力的改变。证明 Bcl-XL 抑制 VDAC1（Monaco et al. 2015 ；Bittremieux et al. 2016 ；Shimizu et al. 2000 ；Li et al. 2008 ）。

Nevertheless, VDAC1 in hepatocarcinoma tissues can be downregulated by the small noncoding RNA miR-7, influencing tumor proliferation and metastasis (Chaudhuri et al. 2016a; Bargaje et al. 2012). Chaudhuri et al. showed that in human neuroblastoma cells and in mouse primary cortical neurons, miR-7 can reduce VDAC1 expression, with consequent inhibition of mitochondrial Ca²⁺ uptake, membrane depolarization, mitochondrial fragmentation, cytochrome c release, and ROS production, promoting cancer cell survival (Chaudhuri et al. 2016a).
然而，肝癌组织中的VDAC1可以被小非编码RNA miR-7下调，影响肿瘤增殖和转移（Chaudhuri et al. 2016a ；Bargaje et al. 2012 ）。乔杜里等人。研究表明，在人神经母细胞瘤细胞和小鼠原代皮质神经元中，miR-7 可以降低 VDAC1 表达，从而抑制线粒体 Ca ²⁺摄取、膜去极化、线粒体碎片、细胞色素 c 释放和 ROS 产生，促进癌细胞存活。乔胡里等人， 2016a ）。

MCU allows calcium ion permeation into the mitochondrial matrix, and its overexpression leads to an increase in mitochondrial Ca²⁺ entry and ROS production, influencing the migration, invasion, and size of different tumor types (Yu et al. 2017; Tang et al. 2015; Wang et al. 2007). However, a reduction in MCU expression decreases mitochondrial Ca²⁺ uptake, the opening of the mPTP and the release of proapoptotic factors, thus having a protective effect on apoptosis (Marchi et al. 2019b; Sebag et al. 2018; Oropeza-Almazan et al. 2017; Yuan et al. 2017; Liao et al. 2015; Qiu et al. 2013; Penston and Wormsley 1986).
MCU允许钙离子渗透到线粒体基质中，其过度表达导致线粒体Ca ²⁺进入和ROS产生增加，影响不同肿瘤类型的迁移、侵袭和大小(Yu et al. 2017 ；Tang et al. 2017 ) 2015 ；王等人， 2007 ）。然而，MCU表达的减少会减少线粒体Ca ^{2+ 的}摄取、mPTP的开放和促凋亡因子的释放，从而对细胞凋亡具有保护作用(Marchi et al. 2019b ; Sebag et al. 2018 ; Oropeza-Almazan et al. 2018 ; Oropeza-Almazan et al.袁等人，2017 ；邱等人， 2013 ；

Marchi et al. showed that, through MCU downregulation, the miR-25 MCU-targeting microRNA could perturb Ca²⁺ homeostasis, reducing the concentration of mitochondrial Ca²⁺ levels in HeLa cells. However, high levels of miR-25 have been observed both in prostate and colon cancer. The miR-25-dependent reduction in mitochondrial Ca²⁺ uptake correlates with resistance to proapoptotic stimuli and can be reversed by anti-miR-25 overexpression. Treatment with anti-miR-25 can restore the MCU expression levels and reverse the pathophysiology, thus suggesting a novel therapeutic target for prostate and colon cancer (Marchi et al. 2013).
马尔基等人。结果表明，通过 MCU 下调，靶向 miR-25 MCU 的 microRNA 可以扰乱 Ca ²⁺稳态，降低 HeLa 细胞中线粒体 Ca ²⁺水平的浓度。然而，在前列腺癌和结肠癌中均观察到高水平的 miR-25。线粒体 Ca ²⁺摄取的 miR-25 依赖性减少与促凋亡刺激的抵抗相关，并且可以通过抗 miR-25 过表达来逆转。抗 miR-25 治疗可以恢复 MCU 表达水平并逆转病理生理学，从而提出前列腺癌和结肠癌的新治疗靶点 (Marchi et al. 2013 )。

One gene that is frequently deleted in many human cancers, principally in those caused by environmental carcinogens, is fragile histidine triad (FHIT). Consequently, its product, the Fhit protein, is absent or reduced in most cancers (Huebner and Croce 2003). The Fhit protein is localized in the mitochondria and the cytosol and acts as a tumor suppressor, increasing susceptibility to apoptosis (Siprashvili et al. 1997). Reintroduction of Fhit to the highly carcinogen-susceptible Fhit^−/− mouse model reduced tumor sizes by activating apoptotic cell death (Zanesi et al. 2005). The Fhit protein generates ROS and enhances mitochondrial Ca²⁺ uptake by increasing mitochondrial Ca²⁺ hotspots. Therefore, Fhit acts as a tumor suppressor by modulating MCU opening and enhancing the susceptibility of cells to apoptosis, thus potentiating the effect of apoptotic agents (Rimessi et al. 2009).
在许多人类癌症（主要是由环境致癌物引起的癌症）中经常被删除的一种基因是脆性组氨酸三联体（FHIT）。因此，其产物 Fhit 蛋白在大多数癌症中不存在或减少（Huebner 和 Croce 2003 ）。 Fhit 蛋白位于线粒体和细胞质中，充当肿瘤抑制因子，增加细胞凋亡的易感性（Siprashvili 等人， 1997 ）。将 Fhit 重新引入高度致癌物敏感的 Fhit ^-/−小鼠模型中，可通过激活细胞凋亡来减小肿瘤大小（Zanesi 等人， 2005 ）。 Fhit 蛋白产生 ROS 并通过增加线粒体 Ca ²⁺热点来增强线粒体 Ca ²⁺吸收。因此，Fhit通过调节MCU开放并增强细胞对细胞凋亡的敏感性来充当肿瘤抑制剂，从而增强细胞凋亡剂的作用（Rimessi等人， 2009 ）。

Transient receptor potential cation channel subfamily C member 3 (TRPC3) belongs to a group of nonselective cation channels that are involved in different cellular mechanisms. TRPC3 channels can influence the mitochondrial membrane potential following their up- and downregulation. The activation of Ca²⁺-sensitive downstream pathways occurs through the influx of calcium from transient receptor potential channels (TRP channels), which act as apoptotic regulators (Wang et al. 2019; Takahashi et al. 2018; Raphael et al. 2014; Monet et al. 2010). However, Shengjie Feng et al. have shown that a fraction of the TRPC3 protein is localized to the mitochondria and mediates mitochondrial Ca²⁺ uptake when the cytosolic calcium concentration is elevated. Since, as we previously noted, mitochondrial membrane potential seems to be affected by TRPC3 channels and because mitochondrial Ca²⁺ uptake is not abolished when MCU expression is downregulated (De Stefani et al. 2011), TRPC3 might be another channel that allows the entry of calcium into the mitochondria, in addition to MCU (Kirichok et al. 2004). In particular, resistance to apoptosis and the proliferation of some tumors could be related to its downregulation, which results in reduced mitochondrial calcium uptake (Feng et al. 2013).
瞬时受体电位阳离子通道亚家族 C 成员 3 (TRPC3) 属于一组参与不同细胞机制的非选择性阳离子通道。 TRPC3 通道的上调和下调可以影响线粒体膜电位。 Ca ²⁺敏感下游通路的激活是通过钙从瞬时受体电位通道（TRP 通道）流入而发生的，瞬时受体电位通道充当细胞凋亡调节剂（Wang 等人， 2019 年；Takahashi 等人， 2018 年；Raphael 等人， 2014 年；莫奈等人， 2010 ）。然而，冯胜杰等人。已经表明，TRPC3 蛋白的一部分定位于线粒体，并在细胞质钙浓度升高时介导线粒体 Ca ²⁺摄取。正如我们之前指出的，由于线粒体膜电位似乎受到 TRPC3 通道的影响，并且当 MCU 表达下调时，线粒体 Ca ²⁺摄取不会被消除（De Stefani 等人， 2011 ），TRPC3 可能是允许进入的另一个通道除了 MCU 之外，还包括钙进入线粒体（Kirichok 等人， 2004 ）。特别是，一些肿瘤对细胞凋亡和增殖的抵抗可能与其下调有关，从而导致线粒体钙摄取减少（Feng et al. 2013 ）。

Fetal and adult testis-expressed 1 protein (FATE1) is a 21-kDa protein that belongs to the cancer-testis antigen proteins that are mainly expressed in the testis under physiological conditions and are upregulated in different cancer types (Dong et al. 2003; Whitehurst 2014; Simpson et al. 2005). This molecule, being a member of the mitochondrial fission factor (Miff) protein family, shares some structural similarities with Mff (Gandre-Babbe and van der Bliek 2008). The oncoprotein FATE1, which is located on the mitochondrial outer membrane preferentially in the MAMs compartment, is implicated in the regulation of Ca²⁺-dependent apoptosis in cancer cells, acting as an anti-tether agent through the modulation of the distance between the ER and the mitochondria (Doghman-Bouguerra et al. 2016), being a direct connection between its increased expression and MAMs morphology in adrenocortical carcinoma (AAC) patients with a poor prognosis (Doghman-Bouguerra et al. 2016). Overexpression of FATE1 in adenoid cystic carcinoma (ACC) was related to a decrease in mitochondrial Ca²⁺ uptake that confers resistance to proapoptotic stimuli and chemotherapeutic drugs (Doghman-Bouguerra et al. 2016).
胎儿和成人睾丸表达1蛋白（FATE1）是一种21-kDa蛋白，属于癌症睾丸抗原蛋白，在生理条件下主要在睾丸中表达，并且在不同癌症类型中表达上调（Dong et al. 2003 ；怀特赫斯特2014 ；辛普森等人2005 ）。该分子是线粒体裂变因子 (Miff) 蛋白家族的成员，与 Mff 有一些结构相似性 (Gandre-Babbe 和 van der Bliek 2008 )。癌蛋白 FATE1 优先位于 MAM 区室中的线粒体外膜上，参与癌细胞中 Ca ²⁺依赖性细胞凋亡的调节，通过调节 ER 之间的距离充当抗束缚剂。和线粒体 (Doghman-Bouguerra et al. 2016 )，在预后不良的肾上腺皮质癌 (AAC) 患者中，其表达增加与 MAM 形态之间有直接联系（Doghman-Bouguerra 等人， 2016 年）。 FATE1 在腺样囊性癌 (ACC) 中的过度表达与线粒体 Ca ²⁺摄取减少有关，从而赋予对促凋亡刺激和化疗药物的抵抗力 (Doghman-Bouguerra et al. 2016 )。

In most human cancer types, including head and neck squamous cell carcinoma (HNSCC), high levels of enhancer of zeste homolog 2 (EZH2) have been detected. EZH2 is the enzymatic subunit of the PRC2 complex (polycomb repressive complex 2), which methylates lysine 9 and lysine 27 of histone H3, and is fundamental for transcriptional repression (Kim and Roberts 2016; Schuettengruber et al. 2007; Boyer et al. 2006). EZH2 acts as an oncogene, and its high expression levels are associated with tumor cell proliferation and migration (Zhou et al. 2015a; Ning et al. 2015). Furthermore, it has been shown that inhibition of EZH2 in HNSCC cells in vitro and in vivo induces loss of mitochondrial membrane potential (ΔΨ_m) with consequent activation of cell death pathways. Inhibition of EZH2 involves accumulation of Ca²⁺ into the mitochondria, induced by inactivation of MICU1 (Zhou et al. 2015b; Cosentino and Garcia-Saez 2014) (Fig. 1).
在大多数人类癌症类型中，包括头颈鳞状细胞癌 (HNSCC)，已检测到高水平的 zeste 同源物增强子 2 (EZH2)。 EZH2 是 PRC2 复合物（多梳抑制复合物 2）的酶亚基，可甲基化组蛋白 H3 的赖氨酸 9 和赖氨酸 27，并且是转录抑制的基础（Kim 和 Roberts 2016 ；Schuettengruber 等人2007 ；Boyer 等人2006））。 EZH2作为癌基因，其高表达水平与肿瘤细胞增殖和迁移相关(Zhou et al. 2015a ；Ning et al. 2015 )。此外，研究表明，体外和体内抑制 HNSCC 细胞中的 EZH2 会导致线粒体膜电位 (ΔΨ _m ) 丧失，从而激活细胞死亡途径。 EZH2的抑制涉及由MICU1失活诱导的Ca ²⁺积累到线粒体中（Zhou等人2015b ；Cosentino和Garcia-Saez 2014 ）（图1 ）。

4 Upregulation of ER-Mitochondria Ca²⁺ Crosstalk
4 ER-线粒体 Ca ²⁺串扰的上调

4.1 New Insights into Ca²⁺ Signaling Perturbation in the MAMs
4.1对 MAM 中 Ca ²⁺信号传导扰动的新见解

The numerous molecular pathways described thus far all involve a decreased uptake of Ca²⁺ to the mitochondria, resulting from decreased ER release or mitochondrial defects. Historically, reports that have assessed the remodeling of MAMs Ca²⁺ signaling associated with tumorigenesis, invasion, and metastasis all led to the conclusion that cancer cells undergo minor mitochondria-dependent apoptosis because of decreases in the Ca²⁺ release from the ER. Recently, the characterization of new MAM-localized proteins and the finding of new mechanisms of action led the scientific community to consider that even an upregulation of Ca²⁺ signaling at the MAMs level could be harmful and drive tumor onset and progression. In the following paragraphs, we will describe how this condition, hitherto described as the cause of apoptotic cell death, can lead to the onset and development of tumor diseases.
迄今为止描述的众多分子途径都涉及线粒体对 Ca ²⁺的吸收减少，这是由于 ER 释放减少或线粒体缺陷所致。历史上，评估与肿瘤发生、侵袭和转移相关的 MAM Ca ²⁺信号重塑的报告都得出这样的结论：由于 ER 释放的 Ca ²⁺减少，癌细胞会经历轻微的线粒体依赖性细胞凋亡。最近，新的 MAM 定位蛋白的表征和新的作用机制的发现使科学界认为，即使 MAM 水平上的 Ca ²⁺信号传导上调也可能是有害的，并会促进肿瘤的发生和进展。在下面的段落中，我们将描述这种迄今为止被描述为细胞凋亡原因的情况如何导致肿瘤疾病的发生和发展。

4.2 Increased ER-Ca²⁺ Release
4.2 ER-Ca ²⁺释放增加

The endoplasmic reticulum is an organelle that contains a network of tubules and flattened sacs and is mainly known for its major role in the production, processing, and transport of proteins and lipids. The ER also represents the major intracellular store of Ca²⁺, an ion that is necessary on its lumen for second-messenger-induced Ca²⁺ release, the control of capacitative Ca²⁺ influx, and intra-ER chaperone activities such as polypeptide translocation, protein folding, and ER-associated degradation (Buck et al. 2007). In normal tissue cells, a sustained Ca²⁺ flux from the ER to the mitochondria can enhance the sensitivity of mitochondria to apoptotic stimuli; however, in some cases, an increase in Ca²⁺ ion leakage from the ER to the MAMs can promote tumor formation, especially in specific tissues and organs. For ER-mitochondria interorganellar Ca²⁺ signaling and, in particular, increased ER Ca²⁺ release, the recent revelation of the mechanisms by which IP3R3 upregulation drives oncogenesis via ER-mitochondrial Ca²⁺ crosstalk is particularly important. This statement is particularly strong because until last year, IP3R3 was well characterized as a Ca²⁺-related proapoptotic protein. In fact, the tumor suppressors BAP1 and PTEN have a stabilizing effect on IP3R3 in the ER, promoting susceptibility to cell death (Bononi et al. 2017; Kuchay et al. 2017), and in contrast, the oncogene K-Ras^G13D downregulates IP3R3, preventing the apoptotic death of cancer cells (Pierro et al. 2014). Three recent works by Guerra et al. (2019), Rezuchova et al. (2019), and Ueasilamongkol et al. (2020), for the first time, have deviated from the idea that IP3Rs only have an anti-oncogenic potential by driving proapoptotic Ca²⁺ signals to mitochondria but attributed an oncogenic potential to ER-mitochondria Ca²⁺ crosstalk. In an analysis of tumor tissues, the IP3R3-protein levels were elevated in hepatocellular carcinoma biopsies compared to healthy liver biopsies (Guerra et al. 2019), in clear cell renal cell carcinoma kidney biopsies compared to healthy regions (Rezuchova et al. 2019) and in cholangiocarcinoma cancer biopsies and cancer cell lines compared to normal tissues and normal cholangiocyte cell models (Ueasilamongkol et al. 2020). In all cases, only type 3 IP3Rs were found to be overexpressed in tumor tissues, with no changes or slight downregulation of type 1 and type 2. In particular, IP3R3 seems to be completely absent in normal human hepatocytes but is clearly present in biopsies from individuals with hepatitis B virus, hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD), which are the four most common predisposing factors to the development of hepatocellular carcinoma (Guerra et al. 2019). This increase was more pronounced in the late stages of hepatocellular carcinoma.
内质网是一种细胞器，包含小管和扁平囊网络，主要因其在蛋白质和脂质的生产、加工和运输中的重要作用而闻名。 ER 还代表 Ca ²⁺的主要细胞内储存，Ca 2+ 是其管腔上第二信使诱导的 Ca ²⁺释放、控制电容性 Ca ²⁺流入和内质网内分子伴侣活性（如多肽）所必需的离子。易位、蛋白质折叠和 ER 相关降解（Buck 等人， 2007 ）。在正常组织细胞中，从内质网到线粒体的持续Ca ²⁺通量可以增强线粒体对凋亡刺激的敏感性；然而，在某些情况下，Ca ²⁺离子从 ER 渗漏至 MAM 的增加可促进肿瘤形成，特别是在特定组织和器官中。对于 ER-线粒体细胞间 Ca ²⁺信号传导，特别是增加 ER Ca ²⁺释放，最近揭示的 IP3R3 上调通过 ER-线粒体 Ca ²⁺串扰驱动肿瘤发生的机制尤为重要。这种说法特别有力，因为直到去年，IP3R3 才被充分表征为 Ca ²⁺相关促凋亡蛋白。事实上，肿瘤抑制因子 BAP1 和 PTEN 对 ER 中的 IP3R3 具有稳定作用，促进细胞死亡的易感性 (Bononi et al. 2017 ; Kuchay et al. 2017 )，相反，癌基因 K-Ras ^G13D下调 IP3R3 ，防止癌细胞凋亡（Pierro et al. 2014 ）。 Guerra 等人最近的三部作品。 ( 2019 )，Rezuchova 等人。（ 2019 ）和Ueasilamongkol等人。 ( 2020 ) 首次偏离了 IP3R 仅通过向线粒体驱动促凋亡 Ca ²⁺信号而具有抗癌潜力的观点，而是将致癌潜力归因于 ER-线粒体 Ca ²⁺串扰。在对肿瘤组织的分析中，与健康肝脏活检组织相比，肝细胞癌活检组织中的 IP3R3 蛋白水平升高（Guerra et al. 2019 ），与健康区域相比，透明细胞肾细胞癌肾活检组织中的 IP3R3 蛋白水平升高（Rezuchova et al. 2019 ）以及胆管癌癌症活检和癌细胞系与正常组织和正常胆管细胞模型的比较（Ueasilamongkol et al. 2020 ）。在所有情况下，仅发现 3 型 IP3R 在肿瘤组织中过度表达，1 型和 2 型没有变化或略有下调。特别是，IP3R3 似乎在正常人肝细胞中完全不存在，但在活检组织中明显存在。患有乙型肝炎病毒、丙型肝炎病毒（HCV）、非酒精性脂肪肝病（NAFLD）和酒精性肝病（ALD）的个体，这是发生肝细胞癌的四种最常见的诱发因素（Guerra等，2017）。 2019 ）。这种增加在肝细胞癌晚期更为明显。

Notably, in cholangiocarcinoma cells, most IP3R3 is localized to the MAMs, while in normal cholangiocytes, it resides in the ER subapical pole. In these cells, MAM localization promotes basal respiration by increasing mitochondrial Ca²⁺ signaling, and thus, depletion of this channel in these cells is deleterious for nuclear and mitochondrial functionality (Ueasilamongkol et al. 2020). In HepG2 cells, IP3R3 upregulation promotes cell death, but its chronic overexpression can increase the resistance of these cells to cell death inducers, enhancing malignant cell survival (Guerra et al. 2019).
值得注意的是，在胆管癌细胞中，大多数 IP3R3 定位于 MAM，而在正常胆管细胞中，它位于 ER 根尖下极。在这些细胞中，MAM 定位通过增加线粒体 Ca ²⁺信号传导来促进基础呼吸，因此，这些细胞中该通道的耗尽对核和线粒体功能有害 (Ueasilamongkol et al. 2020 )。在 HepG2 细胞中，IP3R3 上调会促进细胞死亡，但其长期过度表达可以增加这些细胞对细胞死亡诱导剂的抵抗力，从而增强恶性细胞的存活率 (Guerra et al. 2019 )。

The common key in all these cases is the extreme adaptation ability that drives oncogenesis and malignant cell transformation. These cancer cells became addicted to high IP3R3 levels at the MAM compartment for their survival, to maintain sustained cell metabolism and to obtain malignant features such as increased motility, migration, and invasion.
所有这些情况的共同关键是驱动肿瘤发生和恶性细胞转化的极端适应能力。这些癌细胞对 MAM 区室中高水平的 IP3R3 上瘾，以求生存、维持持续的细胞代谢并获得恶性特征，例如运动、迁移和侵袭增加。

We want to include in this section the already mentioned ERO1-α, an extensively studied protein due to its ability to regulate many processes. ERO1-α is particularly enriched at the ER-mitochondria interface, controlling ER redox homeostasis and oxidative folding and regulating Ca²⁺ efflux from the ER and, consequently, mitochondrial Ca²⁺ accumulation (Anelli et al. 2012). ERO1-α is highly expressed in different tumor types and is associated with a poor prognosis in breast cancer (Kutomi et al. 2013). In fact, the expression of ERO1-α in triple-negative breast cancer cells is correlated with that of programmed cell death-ligand 1 (PD-L1), both at the protein and mRNA levels, via hypoxia-inducible factor 1-α (HIF-1α). Depletion of ERO1-α led to a significant reduction in PD-L1-mediated T-cell apoptosis, suggesting that ERO1-α has a key role in tumor-mediated immunosuppression (Tanaka et al. 2017).
我们希望在本节中包括已经提到的 ERO1-α，这是一种经过广泛研究的蛋白质，因为它能够调节许多过程。 ERO1-α 在 ER-线粒体界面特别富集，控制 ER 氧化还原稳态和氧化折叠，并调节 Ca ²⁺从 ER 流出，从而调节线粒体 Ca ²⁺积累 (Anelli et al. 2012 )。 ERO1-α 在不同的肿瘤类型中高表达，并且与乳腺癌的不良预后相关（Kutomi et al. 2013 ）。事实上，三阴性乳腺癌细胞中 ERO1-α 的表达通过缺氧诱导因子 1-α 在蛋白质和 mRNA 水平上与程序性细胞死亡配体 1 (PD-L1) 的表达相关。 HIF-1α）。 ERO1-α 的耗竭导致 PD-L1 介导的 T 细胞凋亡显着减少，表明 ERO1-α 在肿瘤介导的免疫抑制中具有关键作用 (Tanaka et al. 2017 )。

Another MAMs Ca²⁺- and tumor-related protein that acts at the ER level is the receptor chaperone stress-activated chaperone sigma-1 receptor (Sig1R), which senses ER Ca²⁺ concentrations and regulates cell survival. This protein could be considered “borderline” in this section considering its mechanism of action; in fact, Sig1R is an ER-localized protein that favors the efflux of calcium ions from the endoplasmic reticulum and has been described as being overexpressed in breast cancer, especially in cancer cells with metastatic potential (Gueguinou et al. 2017). ER chaperones are important in maintaining proper intracellular Ca²⁺ levels, protein folding, and the unfolded protein response (UPR) under ER stress conditions (Bartoszewska and Collawn 2020).
另一种在 ER 水平发挥作用的 MAM Ca ²⁺和肿瘤相关蛋白是受体伴侣应激激活伴侣 sigma-1 受体 (Sig1R)，它可感知 ER Ca ²⁺浓度并调节细胞存活。考虑到其作用机制，该蛋白质在本节中可以被视为“边缘”；事实上，Sig1R 是一种内质网定位蛋白，有利于钙离子从内质网流出，并且被描述为在乳腺癌中过度表达，尤其是在具有转移潜力的癌细胞中 (Gueguinou et al. 2017 )。 ER 伴侣对于在内质网应激条件下维持适当的细胞内 Ca ²⁺水平、蛋白质折叠和未折叠蛋白反应 (UPR) 非常重要 (Bartoszewska 和 Collawn 2020 )。

Two MAM-localized chaperones that belong to the heat shock 70 kDa (HSP70) protein family are of considerable importance in Ca²⁺ signaling: chaperone glucose-regulated protein GRP75 and glucose-regulated protein 78 (GRP78, also known as immunoglobulin heavy-chain-binding protein BiP) (Brocchieri et al. 2008; Wadhwa et al. 2002).
属于热休克 70 kDa (HSP70) 蛋白家族的两个 MAM 定位伴侣在 Ca ²⁺信号传导中具有相当重要的作用：伴侣葡萄糖调节蛋白 GRP75 和葡萄糖调节蛋白 78 (GRP78，也称为免疫球蛋白重链) -结合蛋白 BiP）（Brocchieri 等人， 2008 ；Wadhwa 等人， 2002 ）。

GRP75 ensures the juxtaposition between IP3R and VDAC1 in the mitochondrial outer membrane (Szabadkai et al. 2006). Its localization is mainly mitochondrial, but it is also present at low levels in the cytoplasm, nucleus, ER, and Golgi apparatus (Ran et al. 2000; Wadhwa et al. 1995), where it exerts many different functions from the import of unfolded proteins into the mitochondrial matrix to modulation of exocytosis and endocytosis (Flachbartova and Kovacech 2013; Voos and Rottgers 2002; Schneider et al. 1996; Kronidou et al. 1994; Scherer et al. 1992). Sig1Rs are particularly enriched at the MAMs and in normal tissues form a complex with GRP78, another MAM-localized chaperone. GRP78 can bind to misfolded proteins and to unassembled complexes and modulates ER-associated degradation (ERAD), which regulates the UPR (Pfaffenbach and Lee 2011; Wang et al. 2009; Little et al. 1994). Its molecular structure displays two domains: the substrate-binding domain (SBD), involved in binding unfolded peptides, and the nucleotide-binding domain (NBD), which binds ATP to be hydrolyzed to obtain energy to prevent unfolded protein aggregation at the N-terminus (Luo et al. 2006; Lindquist and Craig 1988). GRP78, like almost all other chaperones, is useful for storing ER Ca²⁺ as a high-capacity Ca²⁺-binding protein under physiological conditions (Hendershot 2004).
GRP75 确保线粒体外膜中 IP3R 和 VDAC1 的并置（Szabadkai 等人， 2006 ）。它的定位主要是线粒体，但它也以低水平存在于细胞质、细胞核、内质网和高尔基体中（Ran 等人， 2000 年；Wadhwa 等人， 1995 年），在其中发挥许多不同的功能。蛋白质进入线粒体基质以调节胞吐作用和内吞作用（Flachbartova 和 Kovacech 2013 ；Voos 和 Rottgers 2002 ；Schneider 等人1996 ；Kronidou 等人1994 ；Scherer 等人1992 ）。 Sig1R 在 MAM 中特别富集，并且在正常组织中与 GRP78（另一种 MAM 定位分子伴侣）形成复合物。 GRP78 可以与错误折叠的蛋白质和未组装的复合物结合，并调节 ER 相关降解 (ERAD)，从而调节 UPR (Pfaffenbach 和 Lee 2011 ；Wang 等人2009 ；Little 等人1994 )。其分子结构显示出两个结构域：底物结合结构域（SBD），参与结合未折叠肽；核苷酸结合结构域（NBD），结合ATP进行水解以获得能量，以防止未折叠蛋白在N-上聚集。终点站（Luo et al. 2006 ；Lindquist and Craig 1988 ）。与几乎所有其他伴侣一样，GRP78 可用于在生理条件下将 ER Ca ²⁺存储为高容量 Ca ²⁺结合蛋白（Hendershot 2004 ）。

Szabadkai et al. highlighted the mechanism by which Sig1R, dissociating from BiP, binds IP3R3 following the activation of IP3Rs. This event leads to IP3R3 stabilization at the MAMs and to an enhancement of IP3R3-mediated Ca²⁺ fluxes to the mitochondria (Szabadkai et al. 2006). Although BiP is an excellent target to consider for neuroprotective therapeutic strategies (Enogieru et al. 2019), it also influences how tumor cells survive, proliferate, and develop chemoresistance. During chronic ER stress conditions that involve prolonged ER Ca²⁺ depletion, Sig1R localization changes from the MAMs to the peripheral ER, reducing cellular damage and thus preventing cell death. Another mechanism of Ca²⁺ homeostasis perturbation implemented by Sig1R that has direct consequences on cell invasiveness in breast cancer has been described by Gueguinou et al. (2017). Sig1R favors the migration of cancer cells by forming a functional molecular platform with the calcium-activated K⁺ channels SK3 and ORAI calcium release-activated calcium modulator 1 (Orai1) (Gueguinou et al. 2017) (Fig. 2).
萨巴德凯等人。强调了 IP3R 激活后 Sig1R 从 BiP 解离并结合 IP3R3 的机制。该事件导致IP3R3在MAM处稳定并导致IP3R3介导的Ca ²⁺流向线粒体的增强（Szabadkai等人2006 ）。尽管 BiP 是神经保护治疗策略的绝佳靶点（Enogieru et al. 2019 ），但它也会影响肿瘤细胞的生存、增殖和化疗耐药性。在涉及长期 ER Ca ²⁺耗竭的慢性 ER 应激条件下，Sig1R 定位从 MAM 变为外周 ER，减少细胞损伤，从而防止细胞死亡。 Gueguinou 等人描述了由 Sig1R 实现的 Ca ²⁺稳态扰动的另一种机制，该机制对乳腺癌细胞侵袭性具有直接影响。（ 2017 ）。 Sig1R通过与钙激活的K ⁺通道SK3和ORAI钙释放激活的钙调节剂1（Orai1）形成功能性分子平台来促进癌细胞的迁移（Gueguinou等人， 2017 ）（图2 ）。

4.3 Increased Mitochondrial Ca²⁺ Uptake
4.3增加线粒体 Ca ²⁺摄取

Before the identification of the molecular players forming the MCU complex, the role of mitochondrial Ca²⁺ in cancer progression was simply confined to receiving Ca²⁺ from the ER, thereby regulating the apoptotic response. Low ER Ca²⁺ release results in reduced mitochondrial [Ca²⁺], mPTP inhibition, and resistance to chemotherapeutic-induced cell death. Consistent with this view, many oncogenic factors act at the MAMs to limit ER-mitochondria Ca²⁺ transfer (see the “Downregulation of ER-mitochondria calcium crosstalk” section). However, many mitochondrial Ca²⁺ channels that are responsible for favoring Ca²⁺ accumulation, such as VDACs, are overexpressed, rather than reduced, in cancer (Mazure 2017). These observations suggest that an increased intrinsic capacity of the mitochondrial compartment to accumulate Ca²⁺ could contribute to sustained malignant progression, although, at least theoretically, it predisposes cells to Ca²⁺-induced cell death. The oncogenic mechanisms regulated by mitochondrial Ca²⁺ mainly rely on the association between Ca²⁺ and the formation of mitogenic ROS, as well as pure stimulation of mitochondrial metabolism. Ca²⁺ accumulation activates four mitochondrial dehydrogenases, which in turn stimulate the respiratory chain and hence ATP production (Denton 2009). Thus, as a consequence of increased metabolic activity, ROS are generated inside the matrix, but they fail to trigger cell death, probably due to the superior antioxidant defense that often distinguishes the malignant phenotype (Gorrini et al. 2013).
在确定形成 MCU 复合体的分子参与者之前，线粒体 Ca ²⁺在癌症进展中的作用仅局限于从 ER 接收 Ca ²⁺ ，从而调节细胞凋亡反应。低 ER Ca ²⁺释放导致线粒体 [Ca ²⁺ ] 减少、mPTP 抑制和对化疗诱导的细胞死亡的抵抗。与这一观点一致，许多致癌因素作用于 MAM，限制 ER-线粒体 Ca ²⁺转移（参见“ER-线粒体钙串扰下调”部分）。然而，许多负责 Ca ²⁺积累的线粒体 Ca ²⁺通道（例如 VDAC）在癌症中过度表达，而不是减少 (Mazure 2017 )。这些观察结果表明，线粒体区室积累Ca ²⁺的内在能力增加可能有助于持续的恶性进展，尽管至少在理论上，它使细胞易于发生Ca ²⁺诱导的细胞死亡。线粒体Ca ²⁺调控的致癌机制主要依赖于Ca ²⁺与促有丝分裂ROS形成的关联，以及对线粒体代谢的纯粹刺激。 Ca ²⁺积累会激活四种线粒体脱氢酶，进而刺激呼吸链，从而刺激 ATP 产生 (Denton 2009 )。因此，由于代谢活动增加，ROS在基质内产生，但它们未能触发细胞死亡，这可能是由于通常区分恶性表型的卓越抗氧化防御（Gorrini et al. 2013 ）。

The correlation between augmented mitochondrial Ca²⁺ entry, ROS production, and cancer growth appears evident for tumors overexpressing the uniporter complex pore-forming subunit MCU. Indeed, increased levels of MCU have been reported in different tumors, including breast and hepatocellular carcinomas (Vultur et al. 2018). In breast cancer, MCU-dependent mitochondrial Ca²⁺ entry is associated with ROS overproduction and higher metastatic potential through a mechanism that involves the downstream activation of HIF1-α transcriptional activity (Tosatto et al. 2016). Consistent with these observations, upregulation of MCU in triple-negative breast cancer cells promoted metastasis in an in vivo mouse model by enhancing glycolysis, a series of neoplastic events that is counteracted by the tumor-suppressor activity of miRNA-340 (Yu et al. 2017). Moreover, receptor-interacting protein kinase 1 (RIPK1) binds MCU to promote Ca²⁺ entry and colorectal cancer progression through stimulation of mitochondrial bioenergetics (Zeng et al. 2018). In hepatocellular carcinomas, the Ca²⁺-ROS axis orchestrated by MCU resulted in activation of metalloproteinase-2 (MMP2) (Ren et al. 2017), a zinc-dependent endopeptidase associated with extracellular matrix degradation and metastasis (Shay et al. 2015).
对于过表达单向转运蛋白复合物成孔亚基 MCU 的肿瘤来说，增加的线粒体 Ca ²⁺进入、ROS 产生和癌症生长之间的相关性似乎很明显。事实上，据报道，不同肿瘤中的 MCU 水平有所增加，包括乳腺癌和肝细胞癌 (Vultur et al. 2018 )。在乳腺癌中，MCU 依赖性线粒体 Ca ²⁺进入通过涉及 HIF1-α 转录活性下游激活的机制与 ROS 过量产生和更高的转移潜力相关 (Tosatto et al. 2016 )。与这些观察结果一致，三阴性乳腺癌细胞中 MCU 的上调通过增强糖酵解促进体内小鼠模型的转移，糖酵解是一系列肿瘤事件，可被 miRNA-340 的肿瘤抑制活性抵消（Yu 等，2017）。 2017 ）。此外，受体相互作用蛋白激酶 1 (RIPK1) 与 MCU 结合，通过刺激线粒体生物能促进 Ca ²⁺进入和结直肠癌进展 (Zeng et al. 2018 )。在肝细胞癌中，MCU 协调的 Ca ²⁺ -ROS 轴导致金属蛋白酶-2 (MMP2) 的激活 (Ren et al. 2017 )，这是一种与细胞外基质降解和转移相关的锌依赖性内肽酶 (Shay et al. 2015) ）。

The link between Ca²⁺ and ROS overproduction is also relevant for the cancer-related functions of MICU1, the principal member of the MCU complex that regulates the gating of the channel (Kamer and Mootha 2015). Our group recently showed that MICU1 downregulation, as a result of higher AKT activity, could sustain cancer progression through Ca²⁺-dependent ROS generation (Marchi et al. 2019a). Indeed, loss of MICU1 disinhibits MCU, leading to Ca²⁺ permeation under resting (nonstimulated) conditions and increased mitochondrial ROS levels (Csordas et al. 2013), which could ultimately result in cell death (Mallilankaraman et al. 2012a; Liu et al. 2016). This finding implies that malignant cells showing low MICU1 levels predispose concomitant mechanisms to minimize the detrimental effects induced by ROS. Consistent with this view, MICU1 depletion in normal hepatocytes triggered extensive cell death, but upon pharmacological inhibition of mPTP opening, the loss of MICU1 conferred a strong proliferative advantage (Antony et al. 2016). Moreover, a combination of high mitochondrial Ca²⁺ entry through genetic manipulation of the MCU complex and mPTP closure exacerbated the tumorigenic potential of different cancer cells (Marchi et al. 2019b). Taken together, these observations suggest that variations in the composition of the MCU complex are a key event that cooperates with other oncogenic pathways to favor cancer growth.
Ca ²⁺和 ROS 过量产生之间的联系也与 MICU1 的癌症相关功能相关，MICU1 是调节通道门控的 MCU 复合体的主要成员 (Kamer 和 Mootha 2015 )。我们的小组最近表明，由于 AKT 活性较高，MICU1 下调可以通过 Ca ²⁺依赖性 ROS 生成维持癌症进展 (Marchi et al. 2019a )。事实上，MICU1 的缺失会抑制 MCU，导致静息（未刺激）条件下 Ca ²⁺渗透并增加线粒体 ROS 水平（Csordas 等人， 2013 ），这最终可能导致细胞死亡（Mallilankaraman 等人， 2012a ；Liu 等人） 2016 ）。这一发现意味着，表现出低 MICU1 水平的恶性细胞容易产生伴随机制，以最大限度地减少 ROS 引起的有害影响。与这一观点一致，正常肝细胞中MICU1的缺失引发了广泛的细胞死亡，但在药理抑制mPTP开放后，MICU1的缺失赋予了强大的增殖优势（Antony et al. 2016 ）。此外，通过对 MCU 复合体进行基因操作和 mPTP 关闭来实现高线粒体 Ca ²⁺进入，加剧了不同癌细胞的致瘤潜力（Marchi 等人， 2019b ）。综上所述，这些观察结果表明，MCU 复合体组成的变化是与其他致癌途径协同促进癌症生长的关键事件。

Further evidence that supports this scenario derives from the protumorigenic role of MCU regulator 1 (MCUR1), which has been described as a matrix-located, positive regulator of the uniporter complex (Mallilankaraman et al. 2012b). In hepatocellular carcinomas, MCUR1 was strongly upregulated, and ROS production was augmented, leading to ROS-dependent degradation of p53 and consequent resistance to apoptosis (Ren et al. 2018). Notably, the cancer cell detoxification capacity was also increased due to activation of nuclear factor erythroid 2-related factor 2 (NRF2) (Jin et al. 2019), a master gene in the orchestration of the cellular antioxidant response (Cuadrado et al. 2019). Thus, MCUR1 can regulate two cancer hallmarks at once: Ca²⁺-mediated metastatic potential and resistance to apoptosis. However, the expression of MCUR1 correlates with the permeability transition and reduced cell survival (Chaudhuri et al. 2016b), indicating that MCUR1 oncogenic activities might be solely due to the concomitant inhibition of the functions of the mPTP through a superior mechanism. Nevertheless, it has been proposed that MCUR1 could act as a complex IV assembly factor rather than as an MCU interactor (Paupe et al. 2015). In this context, variations in mitochondrial Ca²⁺ uptake and ROS levels are side products of respiratory chain defects; therefore, the active role of Ca²⁺ in MCUR1-mediated oncogenesis should be completely reevaluated.
支持这种情况的进一步证据来自 MCU 调节器 1 (MCUR1) 的促肿瘤作用，它被描述为位于基质的单向转运蛋白复合物的正调节器 (Mallilankaraman et al. 2012b )。在肝细胞癌中，MCUR1 强烈上调，ROS 产生增加，导致 ROS 依赖性 p53 降解，从而抵抗细胞凋亡 (Ren et al. 2018 )。值得注意的是，由于核因子红细胞 2 相关因子 2 (NRF2) 的激活，癌细胞的解毒能力也有所增强 (Jin et al. 2019 )，这是协调细胞抗氧化反应的主基因 (Cuadrado et al. 2019 ) ）。因此，MCUR1 可以同时调节两个癌症标志：Ca ²⁺介导的转移潜能和细胞凋亡抵抗。然而，MCUR1 的表达与通透性转变和细胞存活率降低相关（Chaudhuri et al. 2016b ），表明 MCUR1 致癌活性可能仅仅是由于通过一种优越的机制同时抑制 mPTP 的功能。尽管如此，有人提出 MCUR1 可以充当复杂的 IV 组装因子，而不是 MCU 相互作用子 (Paupe et al. 2015 )。在这种情况下，线粒体 Ca ²⁺摄取和 ROS 水平的变化是呼吸链缺陷的副产物；因此，Ca ²⁺在MCUR1介导的肿瘤发生中的积极作用应该完全重新评估。

Overall, these observations indicate that increased mitochondrial Ca²⁺ uptake acts with other oncogenic mechanisms (e.g., mPTP inhibition or activation of antioxidant systems) to sustain cancer growth and dissemination. The protumorigenic role of mitochondrial Ca²⁺ signaling involves other pathways in addition to ROS production and excess malignant cell bioenergetics, including the MCU-dependent control of cytosolic Ca²⁺ through store-operated Ca²⁺ entry (SOCE). The activity of the MCU complex sustains cytosolic Ca²⁺ fluxes through SOCE, which in turn regulates cytoskeletal dynamics and cellular migration (Prudent et al. 2016). Moreover, recent findings suggest that spontaneous mitochondrial Ca²⁺ oscillations through the MCU complex are essential for mitotic entry and cell cycle progression (Koval et al. 2019; Zhao et al. 2019), thus revealing another mechanism that could account for the aberrant proliferation of cancer cells with an altered composition of the MCU complex (Fig. 2).
总体而言，这些观察结果表明线粒体Ca ²⁺摄取增加与其他致癌机制（例如，mPTP 抑制或抗氧化系统激活）共同作用，以维持癌症生长和扩散。线粒体 Ca ²⁺信号传导的促肿瘤作用除了 ROS 产生和过量的恶性细胞生物能量外还涉及其他途径，包括通过钙池操纵的 Ca ²⁺进入 (SOCE) 对胞质 Ca ²⁺进行 MCU 依赖性控制。 MCU 复合体的活性通过 SOCE 维持细胞质 Ca ²⁺通量，进而调节细胞骨架动力学和细胞迁移 (Prudent et al. 2016 )。此外，最近的研究结果表明，通过 MCU 复合体的自发线粒体 Ca ²⁺振荡对于有丝分裂进入和细胞周期进展至关重要（Koval et al. 2019 ；Zhao et al. 2019 ），从而揭示了另一种可以解释异常增殖的机制MCU 复合体组成发生改变的癌细胞（图2 ）。

5 Conclusions
5结论

The importance of the multiple and complex signaling pathways generated by the displacement of Ca²⁺ ions and, specifically, the Ca²⁺-dependent communication between structurally and functionally interconnected intracellular organelles has been increasingly highlighted and described, especially in recent years. Evidence of this phenomenon is the dramatic effects on cell health that derive from perturbation of the MAMs morphology and modification of the ER-mitochondria tethering distance. Moreover, alterations in the MAMs protein pool and functionality have been connected with several pathological conditions, including diabetes, neurodegeneration, infection, and antiviral response and cancer (Pinton 2018). Tumor cells, in fact, could modify the systems that maintain cellular Ca²⁺ homeostasis to promote their survival and metastasis. The crucial role of the regulation of spatiotemporal Ca²⁺ signaling in the MAMs in cancer is confirmed by evidence that different oncogenes and tumor suppressors reside at the ER-mitochondria interface.
由Ca ²⁺离子的置换产生的多种复杂信号传导途径的重要性，特别是结构和功能上相互连接的细胞内细胞器之间的Ca ²⁺依赖性通讯，已越来越被强调和描述，特别是近年来。这种现象的证据是 MAM 形态的扰动和 ER-线粒体束缚距离的改变对细胞健康的巨大影响。此外，MAM 蛋白库和功能的改变与多种病理状况有关，包括糖尿病、神经退行性变、感染、抗病毒反应和癌症 (Pinton 2018 )。事实上，肿瘤细胞可以修改维持细胞 Ca ²⁺稳态的系统，以促进其生存和转移。不同癌基因和肿瘤抑制因子位于 ER-线粒体界面的证据证实了癌症中 MAM 中时空 Ca ²⁺信号传导的调节的关键作用。

As shown previously, both an increase and a decrease of calcium ion exchange between these two organelles can, in a nonexclusive way, lead to the promotion or suppression of tumor behaviors in many tissues. This phenomenon is an indication of how the equilibrium that rules calcium homeostasis in this subcellular compartment is delicate, complex, and intimate. Specifically, although Ca²⁺ oscillations are essential at MAMs to feed mitochondrial metabolism, a persistent increase in mitochondrial [Ca²⁺] can lead to cell death. In this scenario, by limiting mitochondrial calcium uptake, many cancer cells develop resistance to death. On the other hand, it was also highlighted that an increased mitochondrial ability to accumulate Ca²⁺ supports malignant progression, by boosting mitochondrial metabolism and sustaining mitogenic ROS production. Thus, depending on the tumor context, MAM-localized Ca²⁺ signaling can exert different functions, also according to the different oncogenic paths involved.
如前所述，这两个细胞器之间钙离子交换的增加和减少都可以以非排他性的方式导致许多组织中肿瘤行为的促进或抑制。这种现象表明，在这个亚细胞区室中，控制钙稳态的平衡是如何微妙、复杂和密切的。具体来说，尽管 Ca ²⁺振荡对于 MAM 促进线粒体代谢至关重要，但线粒体 [Ca ²⁺ ] 的持续增加可能导致细胞死亡。在这种情况下，通过限制线粒体钙的吸收，许多癌细胞产生了对死亡的抵抗力。另一方面，还强调了线粒体积累 Ca ^{2+ 的}能力增加，通过促进线粒体代谢和维持有丝分裂活性氧的产生，支持恶性进展。因此，根据肿瘤背景，MAM 定位的 Ca ²⁺信号传导可以发挥不同的功能，也根据所涉及的不同致癌路径。

Several questions have yet to be answered, many aspects remain to be clarified, and molecular pathways must be described to reach a good understanding of the complex mechanisms that stem from calcium signaling at the MAMs, knowledge that will be very useful in the development of novel therapeutic strategies for several tumors.
有几个问题尚未得到解答，许多方面仍有待澄清，必须描述分子途径，以便更好地理解 MAM 钙信号传导的复杂机制，这些知识对于开发新型药物非常有用。几种肿瘤的治疗策略。

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Acknowledgments

PP is grateful to Camilla degli Scrovegni for continuous support. The Signal Transduction Laboratory is supported by the Italian Association for Cancer Research (AIRC: IG-23670 to P.P. and IG-19803 to C.G.), A-ROSE, Telethon (GGP11139B to P.P), Progetti di Rilevante Interesse Nazionale (PRIN2017E5L5P3 to P.P and PRIN20177E9EPY to C.G.), the Italian Ministry of Health (GR-2013-02356747 to C.G.), the European Research Council (ERC, 853057- InflaPML to C.G.), and local funds from the University of Ferrara to PP and C.G. SM is supported by the Italian Ministry of Health (GR-2016-02364602) and local funds from Marche Polytechnic University (Ancona, Italy). MRW was supported by the Internal Project of The Children’s Memorial Health Institute (No S141/2014).

The authors declare no conflict of interests. All authors read and approved the final version of the manuscript.

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Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
Alberto Danese, Veronica Angela Maria Vitto, Lorenzo Modesti, Sara Leo, Carlotta Giorgi & Paolo Pinton
Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
Saverio Marchi
Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
Mariusz R. Wieckowski

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Alberto Danese
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Department of Biology, University of Copenhagen, København Ø, Denmark
Stine Helene Falsig Pedersen
School of Dentistry, Department of Cell and Tissue Biology, UC San Francisco, San Francisco, CA, USA
Diane L. Barber

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Danese, A. et al. (2020). Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs). In: Pedersen, S.H.F., Barber, D.L. (eds) Organelles in Disease. Reviews of Physiology, Biochemistry and Pharmacology, vol 185. Springer, Cham. https://doi.org/10.1007/112_2020_43

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