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Review 评论

Mitophagy in Parkinson's Disease: From Pathogenesis to Treatment
帕金森病中的线粒体自噬：从发病机制到治疗

Jia Liu , Weijin Liu , Ruolin and Hui Yang
刘佳，刘伟进，若琳和杨辉1 Department of Neurobiology School of Basic Medical Sciences, Beijing Institute for Brain Disorders, Capital
北京脑科学研究所脑基础医学院神经生物学系，首都医科大学脑疾病研究所Medical University, Beijing 100069, China
北京 100069 医科大学，中国2 Center of Parkinson's Disease Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Key
北京帕金森病中心，北京神经再生与修复北京市重点实验室Laboratory on Parkinson's Disease, Key Laboratory for Neurodegenerative Disease of the Ministry of
帕金森病实验室，中国神经退行性疾病部重点实验室Education, Beijing 100069, China
教育，中国北京 100069* Correspondence: huiyang@ccmu.edu.cn; Tel./Fax: +86-10-8395-0374
* 通讯：huiyang@ccmu.edu.cn；电话/传真：+86-10-8395-0374

Received: 29 May 2019; Accepted: 10 July 2019; Published: 12 July 2019
收到日期：2019 年 5 月 29 日；接受日期：2019 年 7 月 10 日；发布日期：2019 年 7 月 12 日

Abstract 摘要

Parkinson's disease (PD) is the second most common neurodegenerative disease. The pathogenesis of PD is complicated and remains obscure, but growing evidence suggests the involvement of mitochondrial and lysosomal dysfunction. Mitophagy, the process of removing damaged mitochondria, is compromised in PD patients and models, and was found to be associated with accelerated neurodegeneration. Several PD-related proteins are known to participate in the regulation of mitophagy, including PINK1 and Parkin. In addition, mutations in several PD-related genes are known to cause mitochondrial defects and neurotoxicity by disturbing mitophagy, indicating that mitophagy is a critical component of PD pathogenesis. Therefore, it is crucial to understand how these genes are involved in mitochondrial quality control or mitophagy regulation in the study of PD pathogenesis and the development of novel treatment strategies. In this review, we will discuss the critical roles of mitophagy in PD pathogenesis, highlighting the potential therapeutic implications of mitophagy regulation.
帕金森病（PD）是第二常见的神经退行性疾病。PD 的发病机制复杂且尚不清楚，但越来越多的证据表明线粒体和溶酶体功能障碍与其有关。线粒体自噬是清除受损线粒体的过程，在 PD 患者和模型中受损，与神经退行性加速有关。已知几种与 PD 相关的蛋白质参与线粒体自噬的调节，包括 PINK1 和 Parkin。此外，已知几种与 PD 相关的基因突变会通过干扰线粒体自噬引起线粒体缺陷和神经毒性，表明线粒体自噬是 PD 发病机制的关键组成部分。因此，在研究 PD 发病机制和开发新的治疗策略时，了解这些基因如何参与线粒体质量控制或线粒体自噬调节至关重要。在本综述中，我们将讨论线粒体自噬在 PD 发病机制中的关键作用，突出线粒体自噬调节的潜在治疗意义。

Keywords: mitophagy; Parkin; Parkinson's disease; PINK1; treatment
关键词：线粒体自噬；Parkin；帕金森病；PINK1；治疗

1. Introduction 1. 简介

Parkinson's disease (PD) is one of the most common neurodegenerative disorders in the world, and is characterized by typical motor deficits, including bradykinesia, tremors, rigidity, and postural instability, and a series of non-motor symptoms such as dysosmia, constipation, and depression. The pathological features of PD include the progressive loss of dopaminergic neurons in the substantia nigrapars compacta (SNpc) and the formation of Lewy bodies [1].
帕金森病（PD）是世界上最常见的神经退行性疾病之一，其特征是典型的运动障碍，包括运动迟缓、震颤、僵硬和姿势不稳，以及一系列非运动症状，如嗅觉障碍、便秘和抑郁。PD 的病理特征包括黑质致密部（SNpc）多巴胺能神经元的进行性丧失和 Lewy 小体的形成[1]。
PD can be subdivided into familial and sporadic PD. Epidemiological studies have shown that about of PD cases are inherited, whereas the remaining cases are sporadic. Although the etiology of PD remains unknown, it is believed to involve both genetic and environmental factors, and is associated with aging [2,3]. Thus far, several proteins have been identified as contributing to PD pathogenesis, including -synuclein ( -syn), Parkin, PTEN-induced putative kinase (PINK)1, DJ-1, Leucine-rich repeat kinase (LRRK) 2, and others (Table 1). Many of these are known to participate in mitochondrial quality control or lysosomal functions [4]. Furthermore, familial PD patients with gene mutations usually show mitochondrial defects and impairment of the autophagic pathway [5-8], indicating that these two elements are critical components of PD pathogenesis.
PD 可以分为家族性和散发性 PD。流行病学研究表明，约 的 PD 病例是遗传的，而其余的病例是散发性的。尽管 PD 的病因尚不清楚，但人们认为它涉及遗传和环境因素，并与衰老有关[2,3]。到目前为止，已经确定了几种蛋白质对 PD 的发病机制起作用，包括 -突触核蛋白( -syn)，Parkin，PTEN 诱导的假定激酶(PINK)1，DJ-1，富含亮氨酸重复激酶(LRRK)2 等(Table 1)。其中许多已知参与线粒体质量控制或溶酶体功能[4]。此外，患有基因突变的家族性 PD 患者通常显示线粒体缺陷和自噬通路受损[5-8]，表明这两个因素是 PD 发病机制的关键组成部分。
Table 1. Overview of Parkinson's disease (PD)-related genes. Genes related to PD pathogenesis are listed in Table 1. The locus of genes, hereditary properties, and the onset of disease are described. AD, autosomal dominant; AR, autosomal recessive.
表 1. 与帕金森病(PD)相关的基因概述。表 1 列出了与 PD 发病机制相关的基因。描述了基因的位点、遗传特性和疾病的发作。AD，常染色体显性；AR，常染色体隐性。
Loci Gene Protein Position Inheritance Onset
PARK1 SNCA Alpha-synuclein α-突触核蛋白 AD, sporadic Early or late 早期或晚期
PARK2 PRKN Parkin AR, sporadic Early
PARK3 Unknown Unknown Late
PARK5 UCHL1
Ubiquitin C-Terminal 泛素 C-末端
Hydrolase L1
4p14 Late
PARK6 PINK1
PTEN-induced
putative kinase 1 假定的激酶 1
1p35-p36 AR Early
PARK7 Protein DJ-1 1p36 AR Early
PARK8 LRRK2
Leucine-rich repeat 亮氨酸富集重复
kinase 2
12q12 AD, sporadic Early or late 早期或晚期
PARK9 ATP13A2 ATPase 13A2 1p36 AR Early
PARK10 Unknown Unknown 1p32 Unknown Unknown
PARK11 GIGYF2
GRB10 interacting GRB10 相互作用
GYF protein 2 GYF 蛋白 2
Late
PARK12 Unknown Unknown Xq21-q25 Unknown Unknown
PARK13 HTRA2 Serine peptidase 2 丝氨酸蛋白酶 2 Late
PARK14 PLA2G6
Phospholipase A2 磷脂酶 A2
Group VI
AR Early
PARK15 FBX07 F-Box protein 7 F-Box 蛋白 7 AR Early
PARK17 VPS35
Vacuolar protein 液泡蛋白
sorting 35
16q11.2 Late
PARK18 EIF4G1
Eukaryotic
translation initiation 开始翻译
factor 4 gamma, 1
因子 4 伽玛，1
3q27.1 Late
PARK19 DNAJC6
DNAJ subfamily C DNAJ 亚家族 C
member 6
AR Early
PARK20 SYNJ1 Synaptojanin-1 AR Early
PARK21 DNAJC13
DNAJ subfamily C DNAJ 亚家族 C
member 13
3q22.1 Early
PARK22 CHCHD2
Coiled
coil-helix-coiled 螺旋-螺旋-螺旋
coil-helix domain 2 螺旋-螺旋结构域 2
7p11.2 Late
PARK23 VPS13C
Vacuolar protein 液泡蛋白
sorting 13 homolog
分拣 13 同源物
AR Early
- Glucocerebrosidase Unknown

2. Mitophagy Pathways 2. 线粒体自噬途径

Mitophagy, the selective degradation of mitochondria via autophagy, is a key process for maintaining mitochondrial homeostasis. Mitochondrial turnover via this mechanism is regarded as a significant mechanism for maintaining neuronal health [9]. However, abnormal mitophagy accompanies neurodegeneration. [10] A growing number of studies have shown that autophagy dysfunction impairs mitochondrial homeostasis, and in turn, mitochondrial defects also impact lysosomal functions, suggesting a complex relationship between these processes. [11] Mitophagy impairment results in the progressive accumulation of defective mitochondria, leading to neuronal
线粒体自噬（Mitophagy）是通过自噬途径选择性降解线粒体的关键过程，对于维持线粒体稳态至关重要。通过这种机制进行线粒体更新被认为是维持神经元健康的重要机制[9]。然而，异常的线粒体自噬伴随着神经退行性疾病[10]。越来越多的研究表明，自噬功能障碍会影响线粒体稳态，反过来，线粒体缺陷也会影响溶酶体功能，这表明这些过程之间存在复杂的关系[11]。线粒体自噬障碍导致缺陷线粒体的逐渐积累，最终导致神经元死亡和神经退行性疾病。
death and eventual neurodegeneration. In this review, we discuss the critical roles of mitophagy in PD pathogenesis, highlighting the potential therapeutic implications of mitophagy regulation.
在本综述中，我们讨论了线粒体自噬在帕金森病发病机制中的关键作用，强调了线粒体自噬调控的潜在治疗意义。
Cells possess several mitophagy mechanisms, and different stresses promote mitophagy in distinct cellular contexts. Indeed, mitophagy can be divided into Parkin-dependent or independent pathways, with some crosstalk between them (Figure 1) [12,13].
细胞具有多种线粒体自噬机制，不同的应激条件在不同的细胞环境中促进线粒体自噬。事实上，线粒体自噬可以分为依赖于 Parkin 或独立于 Parkin 的途径，并且它们之间存在一定的相互作用（图 1）[12,13]。
Healthy mitochondria 健康的线粒体
Figure 1. Mitophagy pathways. Mitophagy can be divided into Parkin-dependent or independent pathways. Under normal conditions, PINK1 localizes to mitochondria and is translocated to the mitochondrial inner membrane (MIM), where it is cleaved and subsequently degraded by an -end rule pathway. However, when mitochondria become depolarized, PINK1 accumulates at the outer mitochondrial membrane (OMM) and recruits Parkin. Activated Parkin leads to the ubiquitination of substrates and the recruitment of autophagy receptors to initiate mitophagy. In addition, Parkin-independent mitophagy includes receptor-mediated and ubiquitin ligase-mediated mitophagy. BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; FUNDC1, FUN14 domain-containing protein 1; NDP52, nuclear dot protein ; NIX, BCL2/adenovirus E1B interacting protein 3 like; OPTN, optineurin; Ub, ubiquitin.
图 1. 线粒体自噬途径。线粒体自噬可以分为依赖 Parkin 和独立于 Parkin 的途径。在正常情况下，PINK1 定位在线粒体上并转位到线粒体内膜（MIM），在那里被剪切并通过一个末端规则途径降解。然而，当线粒体脱极化时，PINK1 在外部线粒体膜（OMM）积累并招募 Parkin。激活的 Parkin 导致底物的泛素化，并招募自噬受体以启动线粒体自噬。此外，独立于 Parkin 的线粒体自噬包括受体介导的和泛素连接酶介导的线粒体自噬。BNIP3，BCL2/腺病毒 E1B 19 kDa 相互作用蛋白 3；FUNDC1，FUN14 结构域含蛋白 1；NDP52，核点蛋白；NIX，BCL2/腺病毒 E1B 相互作用蛋白 3 类似；OPTN，视神经营养因子；Ub，泛素。

2.1. Parkin-Dependent Mitophagy
2.1. 依赖 Parkin 的线粒体自噬

In 2008, the Youle lab first identified the relationship of the PD-related gene Parkin and mitophagy, which was regarded as a landmark study in mitophagy [14]. Subsequently, several studies showed that another PD-related gene, PINK1, also participated in this process [15-17]. PINK1 is a serine/threonine kinase encoded by the PARK6 gene. Parkin is an E3 ubiquitin ligase encoded by the PARK2 gene. Mutations in PINK1 and Parkin result in autosomal recessive PD [18,19]. Loss of function of PINK1 or Parkin causes prominent mitochondrial pathology and loss of dopaminergic neurons [20-22], and subsequent studies discovered a crucial role for PINK1 and Parkin in mitophagy. In the current decade, much research related to PINK1/Parkin-mediated mitophagy has emerged, and this pathway is regarded as the most common and important pathway in mitophagy [23].
2008年，Youle实验室首次确定了与帕金森病相关的基因Parkin和线粒体自噬之间的关系，被认为是线粒体自噬领域的里程碑研究[14]。随后，几项研究表明，另一个与帕金森病相关的基因PINK1也参与了这一过程[15-17]。PINK1是由PARK6基因编码的丝氨酸/苏氨酸激酶。Parkin是由PARK2基因编码的E3泛素连接酶。PINK1和Parkin的突变导致常染色体隐性遗传的帕金森病[18,19]。PINK1或Parkin功能丧失导致明显的线粒体病理和多巴胺能神经元丧失[20-22]，随后的研究发现了PINK1和Parkin在线粒体自噬中的关键作用。在当前的十年中，涉及PINK1/Parkin介导的线粒体自噬的研究大量涌现，这条途径被认为是线粒体自噬中最常见和最重要的途径[23]。
The PINK1/Parkin pathway regulates Ub-dependent mitophagy. The assembly of ubiquitin chains on mitochondria is important for the removal of damaged mitochondria via this pathway. This assembly requires three significant elements: PINK1 as a mitochondrial damage sensor, Parkin as a signal amplifier, and ubiquitin chains as the signal effector [24]. PINK1 has a mitochondrial targeting sequence that can guide it to mitochondria, and it triggers mitophagy by sensing mitochondrial depolarization or the accumulation of reactive oxygen species (ROS). Under normal conditions, PINK1 localizes to mitochondria and is translocated to the mitochondrial inner membrane (MIM), where it is cleaved and inactivated by the MIM protease presenilin-associated rhomboid-like protein (PARL) and subsequently degraded by an N-end rule pathway [25,26]. However, when mitochondria become depolarized, PINK1 cannot be translocated to the MIM and cleaved, resulting in its accumulation at the outer mitochondrial membrane (OMM) and the subsequent recruitment and phosphorylation of Parkin [16], which is localized in the cytoplasm and in an inactivated form in healthy mitochondria [27]. Activated Parkin subsequently leads to the ubiquitination of mitochondrial membrane proteins and the recruitment of autophagy receptors such as optineurin (OPTN) and nuclear dot protein (NDP52) to mitochondria [28,29], followed by the formation of LC3-positive phagophores that degrade mitochondria via the lysosome [14,24].
PINK1/Parkin通路调节Ub依赖的线粒体自噬。在这条通路中，泛素链在线粒体上的组装对于通过这条通路清除受损线粒体非常重要。这个组装需要三个重要的元素：作为线粒体损伤传感器的PINK1，作为信号放大器的Parkin，以及作为信号效应器的泛素链[24]。PINK1具有线粒体定位序列，可以将其引导到线粒体，并通过感知线粒体去极化或活性氧积累来触发线粒体自噬。在正常情况下，PINK1定位在线粒体并转位到线粒体内膜（MIM），在那里被MIM蛋白酶前体素关联的菱形样蛋白（PARL）剪切和失活，然后通过N-末端规则途径降解[25,26]。然而，当线粒体去极化时，PINK1无法转位到MIM并被剪切，导致其在外线粒体膜（OMM）上积累，并随后招募和磷酸化Parkin[16]，后者在健康线粒体中定位在细胞质中并处于非活化状态[27]。 激活的帕金森随后导致线粒体膜蛋白的泛素化和自噬受体（如 optineurin（OPTN）和核点蛋白（NDP52））对线粒体的招募[28,29]，随后形成 LC3 阳性的吞噬体，通过溶酶体降解线粒体[14,24]。

2.2. Parkin-Independent Mitophagy
2.2. 帕金森独立的线粒体自噬

Although Parkin is considered to be a crucial regulator of mitophagy, growing evidence shows that mitophagy can occur in the absence of Parkin, which is known as Parkin-independent mitophagy [13]. Generally, Parkin-independent mitophagy includes receptor-mediated and ubiquitin ligase-mediated mitophagy.
尽管帕金森被认为是线粒体自噬的关键调节因子，但越来越多的证据表明，在没有帕金森的情况下也可以发生线粒体自噬，这被称为帕金森独立的线粒体自噬[13]。一般来说，帕金森独立的线粒体自噬包括受体介导和泛素连接酶介导的线粒体自噬。

2.2.1. Receptor-Mediated Mitophagy
2.2.1. 受体介导的线粒体自噬

Several protein receptors have a LIR (LC3-interacting region) motif, which allows them to bind to LC3 to induce mitophagy [30]. B-cell lymphoma 2 (BCL2)/adenovirus E1B interacting protein 3 (BNIP3) and its homolog BCL2/adenovirus E1B interacting protein 3 like (NIX/BNIP3L) are BH3-only proteins belonging to the B-cell lymphoma 2 (BCL-2) family, and both of them can induce mitophagy in HeLa cells lacking Parkin expression. They can insert into the OMM via their C-terminus, and their N-terminus has an LIR domain to facilitate binding to LC3 or GABARAP [31,32]. FUN14 domain-containing protein 1 (FUNDC1) is a mitophagy receptor that responds to hypoxia-induced mitophagy; it can localize to the OMM and has an LIR domain allowing its association with LC3 [33]. Autophagy and Beclin 1 regulator 1 (AMBRA1), an upstream autophagy regulator, can interact with LC3 through an LIR motif; interestingly, AMBRA1 can trigger both Parkin-dependent and Parkin-independent mitophagy [34,35]. In addition to these receptors, some lipids can also bind to LC3 to induce mitophagy, such as cardiolipin. Under normal conditions, cardiolipin is localized in the IMM, and it is exported to the OMM upon mitochondrial stress and binds to LC3 to trigger mitophagy directly [36].
几种蛋白质受体具有 LIR（LC3 相互作用区域）基序，使它们能够与 LC3 结合以诱导线粒体自噬[30]。B 细胞淋巴瘤 2（BCL2）/腺病毒 E1B 相互作用蛋白 3（BNIP3）及其同源物 B 细胞淋巴瘤 2（BCL2）/腺病毒 E1B 相互作用蛋白 3 样（NIX/BNIP3L）是属于 B 细胞淋巴瘤 2（BCL-2）家族的 BH3-only 蛋白质，它们都能在缺乏 Parkin 表达的 HeLa 细胞中诱导线粒体自噬。它们可以通过其 C-末端插入 OMM，其 N-末端具有 LIR 结构域以促进与 LC3 或 GABARAP 的结合[31,32]。FUN14 结构域含蛋白质 1（FUNDC1）是一个对缺氧诱导的线粒体自噬做出反应的自噬受体；它可以定位到 OMM 并具有 LIR 结构域，使其能够与 LC3 结合[33]。自噬和 Beclin 1 调节蛋白 1（AMBRA1），一个上游自噬调节蛋白，可以通过 LIR 基序与 LC3 相互作用；有趣的是，AMBRA1 可以触发 Parkin 依赖和 Parkin 非依赖的线粒体自噬[34,35]。除了这些受体外，一些脂质也可以与 LC3 结合以诱导线粒体自噬，例如磷脂酰胆碱。 在正常条件下，心磷脂定位在内膜，而在线粒体应激时被转运到外膜，并与 LC3 结合直接触发线粒体自噬[36]。

2.2.2. Ubiquitin Ligase-Mediated Mitophagy
2.2.2. 泛素连接酶介导的线粒体自噬

An earlier study suggested that Parkin is indispensable for mitophagy induction, but in 2015, researchers found that PINK1 can recruit NDP52 and optineurin to mitochondria to trigger mitophagy directly, independent of Parkin; these data indicate that Parkin is not indispensable for mitophagy, but rather acts to amplify this signal [37]. In addition to Parkin, there are several other ubiquitin E3 ligases that function in mitophagy. A novel E3 ligase called ARIH1 was found to participate in mitophagy in a PINK1-dependent manner [38]. Mitochondrial ubiquitin ligase activator of NF-kB1 (MUL1) is another ubiquitin E3 ligase on the OMM, and it can compensate for the loss of Parkin/PINK1 loss in a PD model to rescue their mutation-induced phenotypes [39]. Synphilin-1 can interact with PINK1 and be recruited to the mitochondria to promote PINK1-dependent mitophagy. This mitophagy pathway was independent of PINK1-mediated phosphorylation and Parkin [40].
早期的研究表明，Parkin 对于线粒体自噬的诱导是不可或缺的，但在 2015 年，研究人员发现 PINK1 可以招募 NDP52 和 optineurin 到线粒体上直接触发线粒体自噬，与 Parkin 无关；这些数据表明 Parkin 对于线粒体自噬并非不可或缺，而是起到放大这个信号的作用[37]。除了 Parkin 外，还有几种泛素 E3 连接酶参与线粒体自噬。一种新型的 E3 连接酶称为 ARIH1 以 PINK1 依赖的方式参与线粒体自噬[38]。线粒体泛素连接酶 NF-kB1 的激活剂（MUL1）是外膜上的另一种泛素 E3 连接酶，它可以在 PD 模型中弥补 Parkin/PINK1 缺失以拯救其突变引起的表型[39]。Synphilin-1 可以与 PINK1 相互作用并被招募到线粒体上促进 PINK1 依赖的线粒体自噬。这种线粒体自噬途径与 PINK1 介导的磷酸化和 Parkin 无关[40]。

3. Mitophagy in PD Pathogenesis
PD 发病中的线粒体自噬

The mitochondrion is the critical organelle for generating energy for cellular processes, and mitochondrial functionality determines whether a cell survives or dies. Disturbances to mitochondrial homeostasis are known to contribute to several neurodegenerative diseases, including PD [41,42]. Mitochondrial respiratory chain deficits, especially reductions in the activity of complex I, were found in post-mortem brains from sporadic PD patients [43], indicating a significant role of mitochondria in PD pathogenesis. In addition, one of the earliest studies observed mitochondria within autophagosomes in the neurons of PD patients, indicating a potential link between autophagy, damaged mitochondria, and PD pathogenesis [44]. Subsequently, abnormal mitophagy was observed in several PD models, including environmental or genetic forms [36,45-50].
线粒体是为细胞过程产生能量的关键细胞器，线粒体功能决定了细胞的生存与死亡。线粒体稳态的紊乱已知会导致多种神经退行性疾病，包括 PD [41,42]。在散发性 PD 患者的尸体大脑中发现线粒体呼吸链缺陷，尤其是复合物 I 活性的降低，表明线粒体在 PD 发病中起着重要作用 [43]。此外，早期研究观察到 PD 患者神经元内存在自噬体中的线粒体，表明自噬、受损线粒体和 PD 发病之间可能存在联系 [44]。随后，在多种 PD 模型中观察到异常的线粒体自噬，包括环境或遗传形式 [36,45-50]。
Most PD-associated gene mutations participate in mitochondrial dysfunction and mitophagy disorder, including PINK1 and Parkin [51] (Table 2). Therefore, a thorough understanding of how these genes participate in mitochondria quality control or mitophagy modulation is critical in the study of PD pathogenesis and for developing new treatment strategies (Figure 2).
大多数与帕金森病相关的基因突变参与了线粒体功能障碍和线粒体自噬紊乱，包括 PINK1 和 Parkin [51]（表 2）。因此，深入了解这些基因如何参与线粒体质量控制或线粒体自噬调节对于研究帕金森病发病机制和开发新的治疗策略至关重要（图 2）。
Table 2. Overview of mitophagy or mitochondrial dynamics deficits in PD transgenic models. Overexpression or deficiency of PD-related genes, including SNCA, PRKN, PINK1, DJ-1, LRRK2, and GBA, contributes to mitophagy or defects in mitochondrial dynamics. -syn, -synuclein; DA, dopaminergic; GBA, glucocerebrosidase; LRRK2, Leucine-rich repeat kinase 2; PINK1, PTEN-induced putative kinase 1.
表 2. 帕金森病转基因模型中线粒体自噬或线粒体动力学缺陷的概述。过表达或缺乏与帕金森病相关的基因，包括 SNCA、PRKN、PINK1、DJ-1、LRRK2 和 GBA，会导致线粒体自噬或线粒体动力学缺陷。α-突触核蛋白，DA，多巴胺能，GBA，酸酯酶；LRRK2，富含亮氨酸重复的激酶 2；PINK1，PTEN 诱导的假定激酶 1。
Gene Model
Motor
Deficits
Loss of DA
Neurons
-syn
Pathology
Mitophagy
Defect
Mitochondrial
Dynamics Defect 动力学缺陷
Wide-type -syn 宽型 -syn
overexpression
+ + + + +
A53T -syn
overexpression
+ + + + +
A30P -syn
overexpression
+ + + - -
PRKN Parkin deficiency Parkin 缺陷 - - - + +
PINK1 PINK1 deficiency PINK1 缺陷 - - - + +
DJ-1 deficiency DJ-1 缺乏 + - - + +
LRRK2
G2019S LRRK2
overexpression
+ + - + +
L1444P GBA
overexpression
+ unknown + + +
GBA deficiency GBA 缺陷 + unknown + + +
Figure 2. PD-related proteins participate in mitophagy. PINK1 accumulates at the outer mitochondrial membrane (OMM) and recruits Parkin to initiate mitophagy. -syn interacts with Miro and upregulates Miro protein levels, leading to excessive, abnormal Miro accumulation on the mitochondrial surface and delayed mitophagy. Mitochondrial localized -syn also promotes cardiolipin exposure on OMM; the latter further recruited LC3 to mitochondria and induced mitophagy. LRRK2 interacts with RAB10, which binds OPTN to induce mitophagy. LRRK2 interacted with Miro and contributed to its removal via mitophagy. NDP52, nuclear dot protein OPTN, optineurin; Ub, ubiquitin.
图 2. 与帕金森病相关的蛋白参与线粒体自噬。PINK1 在外线粒体膜（OMM）积累，并招募 Parkin 启动线粒体自噬。α-突触核蛋白与 Miro 相互作用，并上调 Miro 蛋白水平，导致线粒体表面过度、异常的 Miro 积累和延迟的线粒体自噬。线粒体定位的α-突触核蛋白还促进 OMM 上的心磷脂暴露；后者进一步招募 LC3 到线粒体并诱导线粒体自噬。LRRK2 与 RAB10 相互作用，RAB10 与 OPTN 结合诱导线粒体自噬。LRRK2 与 Miro 相互作用，并通过线粒体自噬促进其去除。NDP52，核点蛋白；OPTN，视神经营养因子；Ub，泛素。

3.1. PINK1 and Parkin
3.1. PINK1 和 Parkin

As mentioned above, PINK1 and Parkin play critical roles in the process of mitophagy. In the following, we will discuss the canonical mitophagy regulation and non-canonical mitophagy regulation mediated by PINK1 and/or Parkin.
如上所述，PINK1 和 Parkin 在线粒体自噬过程中起着关键作用。接下来，我们将讨论由 PINK1 和/或 Parkin 介导的经典线粒体自噬调控和非经典线粒体自噬调控。

3.1.1. Canonical Mitophagy Regulation
3.1.1. 通路性线粒体自噬的规范调控

PINK1-dependent activation of Parkin is the major pathway leading to mitophagy, as described above. PINK1 plays a dual role of phosphorylating Ub and Parkin on damaged mitochondria. PINK1 phosphorylates Ub or poly-Ub chains at serine 65 (Ser65), and Parkin mediates a feed-forward mechanism to produce poly-Ub chains, thereby amplifying mitophagy signals [52]. Therefore, PINK1 and Parkin cooperatively recognize damaged mitochondria with phosphorylated poly-Ub (p-Ub) chains under stress. Studies on human post-mortem brain specimens have shown that distinct pools of p-Ub-positive structures co-localized with markers of mitochondria, autophagy, and lysosomes. Furthermore, p-Ub structures accumulated in the brains of Lewy body disease patients in an age-dependent and Braak stage-dependent manner, suggesting that may be a biomarker for mitochondrial impairment in aging and disease [53]. A recent study showed that a novel mutant of PINK1, I368N, cannot be stabilized on the OMM upon mitochondrial stress due to conformational changes in its active site that fail to allow for polyubiquitination [54]. The RING1-IBR (in-between-RING) domain of Parkin preferentially binds to ubiquitin in a phosphorylation-dependent manner [55]. Another report showed that p-Ub binds to the RING1 of Parkin at His302 and Arg305, and promotes the disengagement of the UBL from RING1 and Parkin phosphorylation [56].
PINK1 依赖的 Parkin 激活是导致线粒体自噬的主要途径，如上所述。PINK1 在受损线粒体上对 Ub 和 Parkin 进行磷酸化，起到双重作用。PINK1 在丝氨酸 65（Ser65）上磷酸化 Ub 或多 Ub 链，而 Parkin 介导了一个正反馈机制来产生多 Ub 链，从而放大线粒体自噬信号[52]。因此，在应激条件下，PINK1 和 Parkin 共同识别具有磷酸化多 Ub（p-Ub）链的受损线粒体。对人类死后脑组织标本的研究显示，p-Ub 阳性结构的不同池与线粒体、自噬和溶酶体标记物共定位。此外，p-Ub 结构在 Lewy 小体病患者的大脑中以年龄和 Braak 分期依赖的方式积累，这表明 可能是衰老和疾病中线粒体损伤的生物标志物[53]。最近的一项研究表明，PINK1 的一种新型突变体 I368N 在线粒体应激时无法稳定在 OMM 上，因为其活性位点的构象变化无法允许多泛素化[54]。 Parkin的RING1-IBR（中间RING）结构域倾向于以磷酸化依赖的方式结合泛素[55]。另一份报告显示，磷酸化的泛素结合到Parkin的RING1上的His302和Arg305，并促进UBL与RING1的分离以及Parkin的磷酸化[56]。
Ubiquitination is a reversible process, and several deubiquitinating enzymes (DUBs) are known to act in mitophagy. In addition to the roles of PINK1 and Parkin, the formation of p-Ub or poly-Ub chains is balanced by the activities of deubiquitinases. DUBs such as USP30 and USP35 oppose mitophagy by eliminating Ub chains generated by Parkin on OMM [57,58]. Parkin interacts with USP8 and removes K6-linked ubiquitin chains to regulate its own activity [59,60]. USP15 is another antagonist of Parkin; it does not affect the ubiquitination or translocation of Parkin, but rather inhibits Parkin-mediated mitochondrial ubiquitination [61]. A recent study showed that PTEN-long (PTEN-L), a novel PTEN isoform, regulated negatively mitophagy by dephosphorylating p-Ub via its protein phosphatase activity. PTEN-L prevented Parkin mitochondrial translocation, allevieated Parkin phosphorylation, inactivated Parkin activity, and further disrupted the feedforward of mitophagy [62,63]. Therefore, the balance between ubiquitination and deubiquitination regulates mitophagy and mitochondrial homeostasis.
泛素化是一个可逆的过程，已知有几种去泛素化酶（DUBs）参与线粒体自噬。除了PINK1和Parkin的作用外，p-Ub或多泛素链的形成也受到去泛素化酶的活性平衡。例如，USP30和USP35等DUBs通过消除Parkin在OMM上生成的泛素链来对抗线粒体自噬[57,58]。Parkin与USP8相互作用，去除K6-连接的泛素链以调节自身活性[59,60]。USP15是Parkin的另一个拮抗剂；它不影响Parkin的泛素化或转位，而是抑制Parkin介导的线粒体泛素化[61]。最近的研究表明，一种新的PTEN异构体PTEN-long（PTEN-L）通过其蛋白磷酸酶活性去磷酸化p-Ub，从而负调控线粒体自噬。PTEN-L阻止Parkin的线粒体转位，减轻Parkin的磷酸化，失活Parkin的活性，并进一步破坏线粒体自噬的正反馈[62,63]。因此，泛素化和去泛素化之间的平衡调节着线粒体自噬和线粒体稳态。
Parkin has an equivalent Ser65 residue that is similar to ubiquitin, and is located within its N-terminal ubiquitin-like (UBL) domain; this residue is phosphorylated by PINK1, resulting in an open and active conformation [27,64]. Three substitutions in the UBL domain of Parkin (G12R, R33Q, and R42P) were found to significantly decrease PINK1 ability to phosphorylate Parkin. Two other UBL domain substitutions (G12R and T55I) increased the autoubiquitination of Parkin, suggesting that these substitutions increase Parkin degradation [65]. Parkin S65N, a PD-associated mutation, cannot be activated by PINK1. In addition, mice overexpressing Parkin S65A, which is a mutant that cannot be phosphorylated by PINK1, exhibit selective motor deficits, highlighting the critical role of Parkin Ser65 phosphorylation in PD pathogenesis [66]. Furthermore, growing evidence has shown that PINK1-Parkin signaling is prominent in dopaminergic neurons compared with other neurons, suggesting the vulnerability of dopaminergic neurons to mitochondrial stress [67].
Parkin具有与泛素类似的等效Ser65残基，位于其N-末端泛素样（UBL）结构域内；PINK1通过磷酸化该残基，导致Parkin呈开放和活性构象[27,64]。发现Parkin的UBL结构域中的三个突变（G12R、R33Q和R42P）显著降低了PINK1磷酸化Parkin的能力。另外，另外两个UBL结构域的突变（G12R和T55I）增加了Parkin的自泛素化，表明这些突变增加了Parkin的降解[65]。与帕金森病相关的突变Parkin S65N无法被PINK1激活。此外，过表达无法被PINK1磷酸化的突变体Parkin S65A的小鼠表现出选择性运动障碍，突显了Parkin Ser65磷酸化在帕金森病发病机制中的关键作用[66]。此外，越来越多的证据表明，与其他神经元相比，PINK1-Parkin信号在多巴胺能神经元中更为突出，表明多巴胺能神经元对线粒体应激的脆弱性[67]。
The activity of PINK1 can be regulated by its post-translational modification. PINK1 can phosphorylate itself to regulate its kinase activity; Ser228 and Ser402 sites can be autophosphorylated on truncated PINK1, but not on full-length PINK1, and these phosphorylated PINK1 residues further regulate the phosphorylation of Parkin and , and are involved in the induction of mitophagy [68]. Mitochondrial dysfunction arises from increased levels of S-nitrosylated PINK1 (SNO-PINK1), which is a specific post-translational modification on PINK1 that inhibits its kinase activity. SNO-PINK1 formation was found to disrupt mitophagy by decreasing Parkin translocation to mitochondria, further contributing to neuron death [69].
PINK1的活性可以通过其翻译后修饰来调节。PINK1可以磷酸化自身以调节其激酶活性；截短的PINK1上的Ser228和Ser402位点可以自磷酸化，但全长的PINK1上不能，这些磷酸化的PINK1残基进一步调节Parkin和 的磷酸化，并参与线粒体自噬的诱导[68]。线粒体功能障碍是由于S-亚硝基化的PINK1（SNO-PINK1）水平增加引起的，这是一种特定的PINK1翻译后修饰，抑制其激酶活性。发现SNO-PINK1的形成破坏了线粒体自噬，通过减少Parkin转位到线粒体，进一步导致神经元死亡[69]。
Despite post-translational modification, PINK1 and Parkin are also modulated by other factors. Several studies demonstrated the interaction between p53 and parkin [70-72]; another study showed that PINK1 can be down-regulated by p53 directly via its transcriptional activity, and further modulated mitophagy [73]. Interestingly, one recent study for the first demonstrated that Parkin could also act upstream to PINK1 via its transcription factor function by the activation of presenilins promoters. It is regarded as a novel feedback loop between Parkin and PINK1 in the control of mitophagy [74].
尽管有后翻译修饰，PINK1 和 Parkin 也受其他因素调节。几项研究表明 p53 和 parkin 之间存在相互作用[70-72]；另一项研究表明 PINK1 可以通过 p53 的转录活性直接下调，并进一步调节线粒体自噬[73]。有趣的是，最近的一项研究首次证明 Parkin 也可以通过其转录因子功能在上游作用于 PINK1，通过激活前蛋白酶促进子的启动子。这被认为是 Parkin 和 PINK1 在线粒体自噬控制中的一种新型反馈环路[74]。

3.1.2. Non-Canonical Mitophagy Regulation
3.1.2. 非规范线粒体自噬调节

In addition to their known roles in mitophagy, Parkin and PINK1 may modulate mitophagy in other ways. The autophagy protein Beclin1 can interact with Parkin in the cytosol, and is involved in Parkin translocation to mitochondria [75]. Similarly, PINK1 also interacts with Beclin1 [76] at the mitochondria-associated membrane (MAM), which is a specific region between the ER and mitochondria involved in mitochondrial quality control, suggesting a novel role for PINK1 in mitophagy regulation [77]. In addition, a recent study showed that dopaminergic neurons and microglia exhibit a high degree of mitophagy, while basal mammalian mitophagy occurs independently of PINK1, suggesting the presence of other, yet-to-be-discovered mitophagy pathways [78].
除了已知的线粒体自噬作用，Parkin 和 PINK1 可能以其他方式调节线粒体自噬。自噬蛋白 Beclin1 可以在细胞质中与 Parkin 相互作用，并参与 Parkin 转位到线粒体[75]。类似地，PINK1 也与 Beclin1 在线粒体相关膜（MAM）上相互作用，MAM 是内质网和线粒体之间的特定区域，参与线粒体质量控制，这表明 PINK1 在线粒体自噬调节中具有新的作用[77]。此外，最近的研究表明，多巴胺能神经元和微胶质细胞表现出较高程度的线粒体自噬，而基础哺乳动物线粒体自噬独立于 PINK1，这表明存在其他尚未发现的线粒体自噬途径[78]。

3.1.3. PINK1/Parkin-Mediated Mitophagy and Mitochondrial Dynamics
3.1.3. PINK1/Parkin 介导的线粒体自噬和线粒体动力学

Mitophagy mediated by PINK1 and Parkin also involves changes in mitochondrial dynamics, which play a significant role in maintaining mitochondrial homeostasis, especially in neurons. Miro is an adaptor located on the outer mitochondrial membrane; it mediates mitochondrial motility under normal conditions, and is removed from damaged mitochondria upon stress to facilitate mitochondrial clearance via mitophagy. Miro turnover on damaged mitochondria is altered in PD patient-derived fibroblasts with Parkin mutations. Mitochondrial dysfunction triggers the Lys27-type ubiquitination of Miro on the OMM in a PINK1-dependent and Parkin-dependent manner. Additionally, Miro can stabilize phosphomutant versions of Parkin on the OMM, suggesting its role as a member of the Parkin receptor complex [79]. PINK1 was found to phosphorylate Miro, and phosphorylated Miro activated the proteasomal degradation of Miro in a Parkin-dependent manner [80]. Interestingly, the PINK1/Parkin pathway can quarantine damaged mitochondria prior to their clearance by preventing mitochondrial movement [81].
PINK1和Parkin介导的线粒体自噬还涉及线粒体动力学的变化，在维持线粒体稳态方面发挥重要作用，尤其是在神经元中。Miro是位于外线粒体膜上的适配器；它在正常情况下介导线粒体运动，并在应激时从受损线粒体上移除，以促进通过线粒体自噬的线粒体清除。带有Parkin突变的帕金森病患者源性成纤维细胞中，受损线粒体上的Miro周转发生改变。线粒体功能障碍以PINK1依赖和Parkin依赖的方式触发Miro在外线粒体膜上的Lys27型泛素化。此外，Miro可以稳定Parkin的磷酸突变版本在外线粒体膜上，表明其作为Parkin受体复合物的成员的作用。发现PINK1可以磷酸化Miro，磷酸化的Miro以Parkin依赖的方式激活Miro的蛋白酶体降解。有趣的是，PINK1/Parkin途径可以通过阻止线粒体运动来隔离受损线粒体，以在其清除之前进行隔离。
Fission and fusion control mitochondrial morphology, and their balance is critical for the mitochondrial network. Growing evidence suggests that PINK1 and Parkin are critical for modulating mitochondrial fission and fusion. Indeed, the mitochondrial fusion proteins mitofusins (MFN) are substrates of PINK1 and Parkin [82]. Parkin can ubiquitinate MFN1/2, and these polyubiquitin chains are phosphorylated by PINK1 in return [83]. The loss of PINK1 and Parkin causes increases in MFN abundance and damaged mitophagy processes in Drosophila [84]. PINK1 and Parkin mutations in PD patient-derived fibroblasts also impaired MFN1/2 ubiquitination [85]. Subsequently, these signals recruited autophagy receptors to mitochondria, such as P62 and optineurin (OPTN), leading to eventual degradation by lysosomes [86]. Parkin also interacts with and ubiquitinates dynamin-related protein 1 (Drp1), which is a critical fission-related protein, to promote its proteasome-dependent degradation independent of mitophagy [87].
裂变和融合控制线粒体形态，它们的平衡对于线粒体网络至关重要。越来越多的证据表明，PINK1和Parkin对调节线粒体裂变和融合至关重要。事实上，线粒体融合蛋白mitofusins（MFN）是PINK1和Parkin的底物[82]。Parkin可以泛素化MFN1/2，而这些多泛素链则被PINK1磷酸化[83]。PINK1和Parkin的缺失导致果蝇中MFN的丰度增加和受损的线粒体自噬过程[84]。PD患者来源的成纤维细胞中的PINK1和Parkin突变也会影响MFN1/2的泛素化[85]。随后，这些信号招募了与线粒体相关的自噬受体，如P62和optineurin（OPTN），最终通过溶酶体降解[86]。Parkin还与与裂变相关的蛋白质dynamin-related protein 1（Drp1）相互作用并泛素化它，以促进其独立于线粒体自噬的蛋白酶体依赖性降解[87]。
MFN2 also functions as an endoplasmic reticulum (ER)-OMM tether, and its phosphorylation and ubiquitination can trigger the disassembly of MFN2 complexes from the OMM to dissociate mitochondria from the ER; these findings raise the possibility of a regulatory mechanism of mitochondria-ER contact related to PINK1/Parkin that is independent of mitophagy [88]. ER and mitochondria are more closely associated in primary fibroblasts from PD patients with Parkin mutations and Parkin knockout (KO) mice compared with controls. Moreover, the abundance of MFN2 in the MAM was found to be elevated in PARK2 KO tissue and was accompanied by increased transfer from the ER to mitochondria, suggesting that Parkin is directly involved in regulating ER-mitochondria contacts [89].
MFN2 还作为内质网（ER）-OMM 连接器发挥作用，其磷酸化和泛素化可以触发 MFN2 复合物从 OMM 解离，将线粒体与 ER 分离；这些发现提出了与 PINK1/Parkin 相关的线粒体-ER 接触调节机制的可能性，该机制与线粒体自噬无关[88]。与对照组相比，帕金森病患者的原代成纤维细胞中的 ER 和线粒体更密切相关，帕金森基因突变和帕金森基因敲除（KO）小鼠中 MFN2 在 MAM 中的丰度也增加，并伴随着从 ER 到线粒体的转运增加，这表明 Parkin 直接参与调节 ER-线粒体接触[89]。

3.2. -Synuclein
3.2. α-突触核蛋白

-Synuclein ( -syn) is the main component of Lewy bodies, and its mutation, duplication, or triplication results in autosomal-dominant PD [90]. -Syn accumulation contributes to dopaminergic neuron death; although the underlying mechanism remains obscure, growing evidence suggests that mitochondrial dysfunction plays a significant role [41]. Many studies have found that -syn could translocate to mitochondria via its N-terminus, and impaired mitochondrial function [91,92]. Moreover, -syn was also found to impair autophagy, particularly mitophagy, and the latter process was further exacerbated by this detrimental mechanism through the impaired removal of dysfunctional mitochondria .
-α-突触核蛋白（ -syn）是Lewy小体的主要成分，其突变、复制或三倍化导致常染色体显性帕金森病[90]。 -syn的积累导致多巴胺能神经元死亡；尽管其潜在机制尚不清楚，但越来越多的证据表明线粒体功能障碍起着重要作用[41]。许多研究发现， -syn可以通过其N-末端转位到线粒体，并导致线粒体功能受损[91,92]。此外， -syn还被发现损害自噬，特别是线粒体自噬，并且通过受损线粒体的清除进一步加剧了后者的过程 。
-Syn can impair mitophagy in numerous ways. In the neurons of PD patients, -syn interacts with Miro via its N-terminus and upregulates Miro protein levels, leading to excessive, abnormal Miro accumulation on the mitochondrial surface and delayed mitophagy, suggesting that Miro is a target of -syn-associated mitochondrial injury [95]. Overexpression of the A53T -syn mutant results in p38 MAPK activation, and this mutant directly phosphorylated Parkin at serine 131 to disturb its function and mitophagy [96]. In A53T -syn-overexpressing mice, -syn accumulates on mitochondria to cause increased mitophagy and neuronal death, while these mitochondrial deficits can be rescued
-Syn可能以多种方式损害线粒体自噬。在帕金森病患者的神经元中，-Syn通过其N-末端与Miro相互作用，并上调Miro蛋白水平，导致线粒体表面过度异常积累和延迟的线粒体自噬，表明Miro是-Syn相关线粒体损伤的靶点[95]。A53T -Syn突变体的过表达导致p38 MAPK激活，并直接磷酸化Parkin的丝氨酸131，干扰其功能和线粒体自噬[96]。在A53T -Syn过表达的小鼠中，-Syn在线粒体上积累，导致线粒体自噬增加和神经元死亡，而这些线粒体缺陷可以被挽救。
by silencing Parkin and overexpressing Mfn2 or a dominant-negative variant of Drp1 [46,97]. In A53T and E46K -syn transgenic mice, -syn accumulates on the mitochondrial membrane and promotes cardiolipin exposure on the mitochondrial surface. Cardiolipin exposure recruited LC3 to mitochondria and induced mitophagy [98]. Yeast overexpressing both the human wild-type SNCA gene and A53T mutant showed enhanced mitophagy activities [99]. These studies indicate the role of abnormal mitophagy in -syn-mediated toxicity.
通过沉默 Parkin 和过表达 Mfn2 或 Drp1 的一个显性负变异体 [46,97]，在 A53T 和 E46K -syn 转基因小鼠中， -syn 在线粒体膜上积累并促进线粒体表面的磷脂酰基胆碱暴露。磷脂酰基胆碱的暴露招募了 LC3 到线粒体并诱导线粒体自噬 [98]。过表达人类野生型 SNCA 基因和 A53T 突变体的酵母显示出增强的线粒体自噬活性 [99]。这些研究表明了异常线粒体自噬在 -syn 介导的毒性中的作用。

3.3. LRRK2

Mutations in LRRK2, which is a member of the leucine-rich kinase family, are a cause of autosomal dominant PD [100]. Growing evidence suggests that mutations in LRRK2 result in abnormal mitophagy, although the mechanism remains controversial. One study showed that the levels of autophagy markers p62 and LC3 were increased in induced pluripotent stem cell-derived dopaminergic neurons from PD patients with the G2019S mutation in LRRK2, which is the most common LRRK2 mutation related to PD, suggesting the involvement of abnormal autophagy in G2019S-induced neurotoxicity [101]. Another study showed that the number of fragmented mitochondria increased and mitophagic clearance was reduced in human neuroepithelial stem cells from PD patients carrying the G2019S mutation [102]. However, another study suggested that G2019S LRRK2 mutations increase mitophagy due to histone deacetylase activation [103]. In addition, a study of human iPSC-derived neurons showed that LRRK2 interacted with Miro and contributed to its removal. The G2019S mutation delayed mitophagy initiation, while the knockdown of Miro rescued the injury caused by G2019S, indicating that Miro is also a target in the mitophagy injury induced by the LRRK2 mutation [104,105].
LRRK2基因突变是常染色体显性帕金森病的原因之一[100]。越来越多的证据表明，LRRK2基因突变会导致异常的线粒体自噬，尽管其机制仍存在争议。一项研究显示，在帕金森病患者诱导多能干细胞分化的多巴胺能神经元中，LRRK2基因中G2019S突变与自噬标志物p62和LC3的水平增加相关，而G2019S突变是与帕金森病最常见的LRRK2突变相关的，这表明异常自噬参与了G2019S诱导的神经毒性[101]。另一项研究显示，在携带G2019S突变的帕金森病患者的人类神经上皮干细胞中，碎裂线粒体的数量增加，线粒体自噬清除减少[102]。然而，另一项研究表明，G2019S突变通过组蛋白去乙酰化酶的激活增加了线粒体自噬[103]。此外，一项人类诱导多能干细胞分化的神经元研究显示，LRRK2与Miro相互作用并促进其去除。 G2019S 突变延迟了线粒体自噬的启动，而 Miro 的沉默抑制了 G2019S 引起的损伤，表明 Miro 也是 LRRK2 突变引起的线粒体自噬损伤的一个靶点[104,105]。
Several studies have suggested a role for LRRK2 in PINK1 and Parkin-mediated mitophagy. A recent study showed that RAB10, a substrate of LRRK2, accumulated on damaged mitochondria in a PINK1-dependent and Parkin-dependent manner. Subsequently, RAB10 was found to bind OPTN to promote its accumulation and subsequently induced mitophagy, indicating that LRRK2 is involved in PINK1-mediated and Parkin-mediated mitophagy via RAB10 [106]. However, a separate study suggested that LRRK2 attenuated PINK1-dependent and Parkin-dependent mitophagic clearance via its kinase activity [107].
几项研究表明 LRRK2 在 PINK1 和 Parkin 介导的线粒体自噬中起到了一定的作用。最近的一项研究显示，LRRK2 的底物 RAB10 以 PINK1 依赖和 Parkin 依赖的方式在受损的线粒体上积累。随后，发现 RAB10 与 OPTN 结合以促进其积累，并随后诱导线粒体自噬，表明 LRRK2 通过 RAB10 参与了 PINK1 介导和 Parkin 介导的线粒体自噬[106]。然而，另一项研究表明，LRRK2 通过其激酶活性减弱了 PINK1 依赖和 Parkin 依赖的线粒体自噬清除[107]。

3.4.

Mutations in DJ-1, which is encoded by the PARK6 gene, cause a rare form of autosomal recessive PD [108]. Upon stress, DJ-1 localizes to mitochondria and acts as a redox sensor/reductase, and its depletion led to mitochondrial deficits and an increase in ROS levels. DJ-1 is regarded as a neuroprotective factor, and mitochondria-localized DJ-1 regulates the clearance of endogenous ROS [109]. DJ-1 deficiency led to an increased level of oxidative stress [110], which is usually associated with mitophagy impairment [111]. The loss of DJ-1 caused increased Parkin recruitment to damaged mitochondria and increased mitophagy, and DJ-1 levels accumulated on mitochondria under oxidative stress conditions dependent on Parkin and PINK1, suggesting a link between DJ-1 and the PINK1/Parkin-mediated pathway [112]. Parkin regulated DJ-1 levels via a signaling cascade implying p53, indicating that p53 and DJ-1 acted acting downstream of parkin [113]. Additionally, a separate study suggested that DJ-1 functioned in parallel with the PINK1/Parkin pathway to maintain mitochondrial function under an oxidative environment [114]. Another study showed mitochondrial defects in DJ-1 knockout flies, which is similar to PINK1 and Parkin mutants. Interestingly, DJ-1 overexpression rescues the phenotype of flies that are deficient for PINK1, but not Parkin. These data also suggest that DJ-1 is critical for mitochondrial function and acts in parallel to or downstream of PINK1 [115].
DJ-1基因突变导致一种罕见的常染色体隐性帕金森病[108]。在应激情况下，DJ-1定位于线粒体并作为氧化还原传感器/还原酶发挥作用，其缺乏导致线粒体功能障碍和ROS水平增加。DJ-1被认为是一种神经保护因子，线粒体定位的DJ-1调节内源性ROS的清除[109]。DJ-1缺乏导致氧化应激水平增加[110]，通常与线粒体自噬障碍相关[111]。DJ-1的丧失导致Parkin在受损线粒体上的招募增加和线粒体自噬增加，而DJ-1水平在氧化应激条件下依赖于Parkin和PINK1在线粒体上积累，暗示DJ-1与PINK1/Parkin介导的途径之间存在联系[112]。Parkin通过一个信号级联调节DJ-1水平，暗示p53，表明p53和DJ-1在Parkin的下游起作用[113]。此外，另一项研究表明，在氧化环境下，DJ-1与PINK1/Parkin途径并行发挥作用以维持线粒体功能[114]。 另一项研究显示，DJ-1 基因敲除果蝇中存在线粒体缺陷，这与 PINK1 和 Parkin 突变体相似。有趣的是，DJ-1 基因过表达可以挽救 PINK1 缺陷果蝇的表型，但不能挽救 Parkin 缺陷果蝇的表型。这些数据还表明，DJ-1 基因对线粒体功能至关重要，并且在 PINK1 基因的下游或平行通路中发挥作用[115]。

3.5. GBA1

GBA1 encodes the lysosomal enzyme glucosylceramidase beta/ -glucocerebrosidase, and its heterozygous mutations are among the most common genetic risk factors of PD [116]. GBA1
GBA1 基因编码溶酶体酶葡萄糖酰胺酶β/β-葡萄糖苷酶，其杂合突变是帕金森病最常见的遗传风险因素之一[116]。
homozygous mutations cause Gaucher's disease (GD), which is the most frequent lysosomal storage disorder, and some GD patients and their relatives show parkinsonian manifestations [117]. It has been estimated that GBA1 mutations lead to a 20 -fold to 30 -fold increased risk of PD, and at least of PD patients have a GBA1 mutation [118]. Autophagy defects have been confirmed in iPSC-derived neurons from GBA1-associated PD patients [119], and mitochondrial function was also impaired in GD patients [120]. Additionally, GBA1 deficiencies resulted in -syn aggregation in PD or GD models and patients [121-123], indicating that GBA1 is involved in -syn pathology and PD pathogenesis, likely by impairing autophagy and mitochondrial function.
同源突变引起高氏病（GD），这是最常见的溶酶体贮积性疾病，一些GD患者及其亲属表现出帕金森症状[117]。据估计，GBA1突变导致帕金森病（PD）的风险增加20倍至30倍，至少 PD患者携带GBA1突变[118]。已经证实GBA1相关PD患者的iPSC衍生神经元存在自噬缺陷[119]，GD患者的线粒体功能也受损[120]。此外，GBA1缺陷导致PD或GD模型和患者中 -syn蛋白聚集[121-123]，表明GBA1参与 -syn病理和PD发病机制，可能通过损害自噬和线粒体功能。
In primary neurons from GBA1-knockout mice, autophagy was impaired and mitochondrial function was profoundly compromised with a reduced membrane potential [123]. In GBA knock-in mice, the L444P mutation results in mitochondrial dysfunction by inhibiting mitochondrial priming and autophagy, which are two critical steps for mitophagy. In type II neuronopathic GD, the downregulation of mitophagy resulted in the accumulation of insoluble -syn deposits [48]. Furthermore, impaired mitophagy and excessive oxidative stress were found in post-mortem brain tissue from PD patients carrying heterozygous GBA mutations, suggesting a link between mitophagy dysfunction and GBA heterozygous mutations [124].
在 GBA1 基因敲除小鼠的原代神经元中，自噬受损且线粒体功能严重受损，膜电位降低 [123]。在 GBA 基因敲入小鼠中，L444P 突变通过抑制线粒体启动和自噬来导致线粒体功能障碍，这是线粒体自噬的两个关键步骤。在 II 型神经病性 Gaucher 病中，线粒体自噬的下调导致不溶性 α-突触核蛋白沉积物的积累 [48]。此外，在携带杂合 GBA 突变的 PD 患者的死后脑组织中发现自噬受损和过度氧化应激，这表明自噬功能障碍与 GBA 杂合突变之间存在联系 [124]。
Vacuolar protein sorting-associated protein 35 (Vps35), which is encoded by PARK17, causes autosomal-dominant, late-onset PD. Vps35 deficiency or mutation resulted in mitochondrial dysfunction and the loss of dopaminergic neurons [8,125]. Vps35 interacts with Parkin, but not with Pink1; furthermore, its overexpression rescues several Parkin-mutant phenotypes [126].
囊泡蛋白分拣相关蛋白 35（Vps35），由 PARK17 基因编码，导致常染色体显性晚发型 PD。Vps35 缺乏或突变导致线粒体功能障碍和多巴胺能神经元丧失 [8,125]。Vps35 与 Parkin 相互作用，但与 Pink1 无关；此外，其过表达可以挽救几种 Parkin 突变的表型 [126]。
F-box only protein 7 (Fbxo7), which is encoded by PARK15, is a PD-related gene. Mutations of Fbxo7 cause autosomal recessive juvenile atypical PD. Studies showed that mutation impairs mitophagy, suggesting that participated in the modulation of mitochondrial homeostasis [127]. Wild-type can promote mitophagy in response to stress, while mutant was found to inhibit mitophagy [128]. Another study found that Fbxo7 participates in mitophagy by interacting with PINK1 and Parkin directly, while its PD-related mutations interfered with this process [129]. A PD-related Fbxo7 mutation also recruited Parkin to damaged mitochondria and promoted its aggregation [130].
F-box only protein 7 (Fbxo7)，由 PARK15 编码，是与帕金森病相关的基因。Fbxo7 的突变导致常染色体隐性遗传的非典型青少年帕金森病。研究表明， 突变影响线粒体自噬，暗示 参与线粒体稳态的调节[127]。野生型 可以在应激反应中促进线粒体自噬，而突变型 被发现抑制线粒体自噬[128]。另一项研究发现，Fbxo7 通过直接与 PINK1 和 Parkin 相互作用参与线粒体自噬，而其与帕金森病相关的突变干扰了这一过程[129]。与帕金森病相关的 Fbxo7 突变还招募 Parkin 到受损的线粒体并促进其聚集[130]。

4. Modulation of Mitophagy in PD Treatment
4. 帕金森病治疗中的线粒体自噬调节

Mitochondrial deficits and autophagy impairment are critical aspects of PD pathogenesis, with impaired mitophagy found in the brains of PD patients and models. Therefore, correcting mitophagy is a promising avenue for the development of efficient treatments for PD. Pharmacological agents that selectively modulate mitophagy are currently lacking, and thus the clinical applicability of this approach remains limited [131]. Although some compounds such as trifluorocarbonylcyanide phenylhydrazone and the combination of antimycin/oligomycin were found to trigger mitophagy, their effects were toxic and non-specific. Therefore, these agents are not suitable for PD treatment [132]. Campanella et al. developed a compound, P62-mediated mitophagy inducer (PMI), that activates endogenous mitophagy without Parkin recruitment or the dissipation of mitochondrial membrane potential. Therefore, PMI has been regarded as a promising chemical candidate [133]. However, whether PMI exerts a therapeutic effect in PD models remains unclear. One recent study suggested that several pathogenic Parkin variants impaired mitophagy, and thus targeting these variants in the design of genotype-specific drugs represents a promising direction [134].
线粒体功能缺陷和自噬障碍是帕金森病发病机制的关键方面，帕金森病患者和模型的大脑中发现了受损的线粒体自噬。因此，纠正线粒体自噬是开发有效的帕金森病治疗方法的有希望途径。目前缺乏选择性调节线粒体自噬的药物，因此这种方法的临床适用性仍然有限[131]。虽然一些化合物如三氟甲基氰苯肼和抗霉素/寡霉素的组合被发现能触发线粒体自噬，但它们的效果具有毒性且非特异性。因此，这些药物不适合帕金森病治疗[132]。Campanella等人开发了一种化合物，P62介导的线粒体自噬诱导剂（PMI），它能激活内源性线粒体自噬，而无需Parkin招募或线粒体膜电位的消散。因此，PMI被认为是一种有希望的化学候选药物[133]。然而，PMI是否在帕金森病模型中产生治疗效果仍不清楚。 最近的一项研究表明，几种致病性 Parkin 变异体会损害线粒体自噬，因此在基因型特异性药物设计中针对这些变异体是一个有前途的方向 [134]。
Thus far, several synthetic and natural chemical compounds have been used to trigger mitophagy for treating PD models [10,135]. An interesting study showed that a carrier with a homozygous Parkin mutation resulting in the loss of functional Parkin had not developed PD by her eighth decade of life, indicating the potential existence of a putative mechanism of protection against PD. Further study showed that this carrier had preserved mitochondrial function, and mitophagy could be mediated by mitochondrial receptor Nip3-like protein X (Nix), which is a pathway independent of
到目前为止，已经使用了几种合成和天然化学物质来触发线粒体自噬以治疗 PD 模型 [10,135]。一项有趣的研究显示，一个携带纯合 Parkin 突变导致功能性 Parkin 丧失的携带者在八十岁时没有患上 PD，这表明存在一种可能的保护机制来抵抗 PD。进一步研究表明，这个携带者保留了线粒体功能，线粒体自噬可以通过线粒体受体 Nip3-like protein X (Nix) 来介导，这是一种独立于 PINK1/Parkin 途径的机制 [136]。这一发现表明，Nix 可能是 PINK1/Parkin 相关 PD 治疗的一个有前途的靶点，因为它可以作为线粒体自噬的替代介导者。
PINK1/Parkin [136]. This finding suggests that Nix may be a promising target for PINK1/Parkin-related PD treatment, because it could serve as an alternative mediator of mitophagy .
The phosphorylation of Parkin and Ub mediated by PINK1 and ubiquitination-mediated Parkin form a feedforward mechanism of mitophagy [52]. Therefore, regulation of the PINK1-Parkin-Ub feedforward loop is a strategy for mitophagy modulation and PD treatment. PTEN-L can dephosphorylate p-Ub and suppress mitophagy via blockage of the feedforward mechanism [63], so the inhibitor of PTEN-L may contribute to mitophagy activation. As mentioned above, USP30, USP35, and USP15 can counteract Parkin activity and regulate mitophagy negatively. The depletion of USP30 enhanced mitochondria degradation in neurons [57]. Similarly, the knockdown of USP35 or USP15 also promoted the mitophagy pathoway . However, another DUB, USP8, may regulate Parkin and mitophagy positively, because it removed K6-linked ubiquitin chains from Parkin preferentially to promote the efficient recruitment of Parkin and induction of mitophagy [60]. Although research targeting the PINK1-Parkin-Ub feedforward loop is still limited, it is a valuable direction in PD treatment (Figure 3).
PINK1和泛素介导的Parkin的磷酸化以及泛素化介导的Parkin形成了线粒体自噬的正反馈机制[52]。因此，调节PINK1-Parkin-Ub正反馈环路是线粒体自噬调控和帕金森病治疗的策略。PTEN-L可以去磷酸化p-Ub并通过阻断正反馈机制抑制线粒体自噬[63]，因此PTEN-L的抑制剂可能有助于激活线粒体自噬。如上所述，USP30、USP35和USP15可以对抗Parkin的活性并负调节线粒体自噬。USP30的耗竭增强了神经元中线粒体的降解[57]。类似地，USP35或USP15的沉默也促进了线粒体自噬途径的进程。然而，另一个DUB，USP8，可能通过优先去除Parkin上的K6-连接泛素链来正调节Parkin和线粒体自噬，从而促进Parkin的高效招募和线粒体自噬的诱导[60]。尽管针对PINK1-Parkin-Ub正反馈环路的研究仍然有限，但它是帕金森病治疗中有价值的方向（图3）。
Figure 3. The PINK1-Parkin-Ub feedforward loop. PINK1, Parkin, and Ub form a feedforward mechanism of mitophagy. Regulation of this feedforward loop is a strategy for mitophagy modulation and PD treatment. PTEN-L dephosphorylate p-Ub and suppress mitophagy via blockage of the feedforward mechanism. USP30, USP35, and USP15 can counteract Parkin activity and regulate mitophagy negatively, while USP8 regulate Parkin and mitophagy positively. PTEN-L, phosphate and tension homology deleted on chromsome ten-long; Ub, ubiquitin; USP, ubiquitin specific protease.
图 3. PINK1-Parkin-Ub 前馈环路。PINK1、Parkin 和 Ub 形成了线粒体自噬的前馈机制。调节这个前馈环路是线粒体自噬调控和 PD 治疗的策略。PTEN-L 通过阻断前馈机制，去磷酸化 p-Ub 并抑制线粒体自噬。USP30、USP35 和 USP15 可以对抗 Parkin 的活性并负调节线粒体自噬，而 USP8 则正调节 Parkin 和线粒体自噬。PTEN-L，磷酸酯酶和张力在染色体十长上的缺失；Ub，泛素；USP，泛素特异性蛋白酶。

5. Conclusions 5. 结论

Many PD-related genes or risk factors are associated with mitophagy defects. There is a strong reciprocal relationship between mitochondria and autophagy, with the impairment of one process usually resulting in damage to the other, and this vicious cycle eventually contributes to the pathogenesis of PD. However, there are some remaining questions. Although the modulation of mitophagy is regarded as a potential approach in PD treatment, whether mitopagy can be specifically targeted is
许多与 PD 相关的基因或风险因素与线粒体自噬缺陷有关。线粒体和自噬之间存在着强烈的相互关系，其中一个过程的损害通常会导致对另一个过程的损害，这种恶性循环最终导致 PD 的发病机制。然而，还有一些未解之谜。虽然调节线粒体自噬被认为是 PD 治疗的潜在方法，但是否可以针对性地靶向线粒体自噬仍然不清楚。
always a question. Although the PINK1-Parkin-Ub feedforward loop is critical for the regulation of mitophagy, its mechanism is still obscure. Despite these, there is a a critical need to understand mitochondrial and lysosomal dysfunction and how their interplay participate in PD pathogenesis, as targeting these crosstalks and restoring mitophagy represent a promising therapeutic approach for PD.
总是一个问题。尽管 PINK1-Parkin-Ub 前馈环对于线粒体自噬的调节至关重要，但其机制仍然不清楚。尽管如此，我们迫切需要了解线粒体和溶酶体功能障碍以及它们在帕金森病发病机制中的相互作用，因为针对这些相互作用并恢复线粒体自噬代表了一种有前途的治疗方法。
Author Contributions: J.L., W.L., R.L. and H.Y. wrote the manuscript.
作者贡献：J.L.，W.L.，R.L.和 H.Y.撰写了本文。
Funding: This research was funded by The National Key R&D Program of China, grant number 2016YFC1306000, and National Natural Science Foundation of China, grant number 81870994.
资助：本研究由中国国家重点研发计划资助，资助号码为 2016YFC1306000，以及中国国家自然科学基金资助，资助号码为 81870994。
Conflicts of Interest: The authors declare no conflict of interest.
利益冲突：作者声明无利益冲突。

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（C）2019年作者。许可证持有人MDPI，瑞士巴塞尔。本文是一篇开放获取文章，根据创作共用署名（CC BY）许可证的条款和条件进行分发（http://creativecommons.org/licenses/by/4.0/）。