线粒体自噬的研究进展

线粒体自噬（mitophagy）是指细胞通过自噬的机制选择性地清除线粒体的过程。选择性清除受损伤或功能不完整的线粒体对于整个线粒体网络的功能完整性和细胞生存来说十分关键。线粒体自噬的异常和很多疾病密切相关,因此对于线粒体自噬的具体分子机制以及生理意义研究有很重要的生物学意义。线粒体自噬的研究是目前生物学领域的研究热点,该文主要综述了近年来在线粒体自噬领域取得的研究进展,旨在为相关领域的研究提供参考。     

线粒体自噬与心肌保护

线粒体自噬是指细胞通过自噬的机制选择性地清除线粒体的过程。通过该途径,细胞可降解并清除受损或功能障碍的线粒体,以维持细胞内线粒体质量和数量的平衡,从而维持细胞稳态。在生理状态及应激状态下,多种因子可调控心肌细胞线粒体自噬,进而发挥保护心肌细胞的作用。本文就线粒体自噬及其调控机制以及其在心肌保护中的作用做一综述。     

PGC-1α在运动调节线粒体自噬中的作用机制研究

线粒体是调节细胞能量代谢和细胞程序性死亡的重要细胞器,通过自噬机制选择性地清除受损线粒体的过程称为线粒体自噬。线粒体自噬在保持线粒体结构与功能完整性方面发挥重要作用。PGC-1α被认为是运动诱导线粒体生物合成的万能调节因子,但对于它在运动诱导线粒体自噬中的研究较少,本文将对PGC-1α在调节运动诱导的线粒体自噬中的作用机制进行探讨。     

线粒体自噬的研究进展

线粒体自噬(mitophagy)是指细胞通过自噬机制选择性清除多余或损伤线粒体的过程,对于线粒体质量控制以及细胞生存具有重要作用。在线粒体自噬的过程中,线粒体自噬受体FUNDCl、Nix、BNIP3,接头蛋白OPTN、NDP52以及去泛素化酶UPS30、UPS8等发挥了重要的调控作用。近年来,研究发现线粒体自噬与神经退行性疾病、脑损伤以及胶质瘤相关。因此,研究线粒体自噬的分子机制具有重要意义。本文就与哺乳动物相关的线粒体自噬分子机制及最新研究进展做一综述。     

线粒体自噬在肿瘤发生发展中的双重作用

线粒体自噬(mitophagy)是一种选择性的宏观自噬形式,线粒体被自噬溶酶体选择性地靶向降解。线粒体自噬用于去除功能失调的线粒体以减轻氧化应激和预防癌的发生,然而,线粒体自噬不仅仅局限于功能失调的线粒体的更新,而且在一些不利条件下(营养供应不足和缺氧)可促进肿瘤细胞的存活,保护细胞免于凋亡或坏死。因此,线粒体自噬是控制癌细胞质量的关键因素。鉴于线粒体自噬的重要作用,越来越多的研究关注线粒体自噬的调控机制,其调控机制主要是相关通路蛋白,同样,药物也能调控线粒体自噬。本文将会从线粒体自噬在肿瘤发生中的双重作用及其调控机制这三方面进行综述,旨在为肿瘤治疗提供新的方向。     

线粒体自噬的分子机制

线粒体自噬指细胞选择性清除受损伤或多余线粒体的一种自噬方式,是线粒体应激反应和线粒体稳态调控的重要部分,对其分子机制以及相应调控机制的研究受到广泛关注.本文总结了近年来关于线粒体自噬的分子机制研究进展,同时分析了相关受体介导线粒体自噬的信号调节机制,以期为将来线粒体自噬研究的发展和完善提供借鉴意义.     

PINK1/parkin通路调控线粒体自噬机制的研究进展

线粒体自噬指细胞通过自噬机制选择性除去损伤或多余的线粒体。真核生物通过线粒体自噬调控线粒体质量,维持供能细胞器的功能。大量研究表明,帕金森病相关基因PINK1和parkin可通过线粒体自噬参与并维持线粒体功能。PINK1与parkin能协同特异性识别损伤的线粒体,PINK1作为线粒体质量调控的探测器被活化,此过程中泛素化酶和去泛素化酶对维持parkin活性及线粒体自噬的效率有重要作用。本文主要总结PINK1/parkin通路在线粒体自噬中的功能与作用。     

氧化应激下植物线粒体自噬分析

线粒体自噬,是指通过选择性的识别并清除损伤、衰老及功能紊乱的线粒体,对维持细胞内线粒体质量和数量的平衡产生了重要作用。与动物和酵母中线粒体自噬的研究进展相比,植物线粒体自噬的途径及具体调控机制尚不明确。基于GFP标签,本文探究了氧化胁迫下植物线粒体自噬发生情况。研究发现甲基紫精诱导线粒体在液泡中积累,并呈现两种状态:1) GFP小体包含的线粒体; 2)不含GFP的线粒体。本研究发展的GFP标签策略可为植物线粒体自噬关键调控因子的筛选提供借鉴。     

线粒体自噬调控机制研究进展

线粒体为细胞正常生命运动提供能量和物质;然而各种因素会导致线粒体损伤,衰老及功能紊乱,它们是细胞潜在的危险因素,必需及时清除,线粒体自噬可以起到这一作用,维持细胞稳态。当细胞处于恶劣环境时,线粒体自噬可通过降解线粒体补充生命必需物质,从而度过危机维持生存。另外线粒体自噬会在某些情况下通过降解正常线粒体来维持线粒体质量和数量的平衡。不同生物中具有不同的线粒体自噬途径和机制,酵母中主要通过Atg32磷酸化调控线粒体自噬;哺乳动物中则存在分别由Parkin-PINK1、Nix、FUNDC1等不同蛋白介导的线粒体自噬调控机制;植物线粒体自噬的研究主要集中在拟南芥,其途径及具体调控机制尚不明确。综述了近年来酵母、动物和植物中线粒体自噬的作用机制及调控因子等方面的研究进展。     

阿尔茨海默症中的线粒体自噬

线粒体自噬是细胞进化过程中产生的一种通过自噬选择性清除受损线粒体的机制,及时清除损伤的线粒体对维持细胞正常生理功能具有重要作用。在阿尔茨海默症(Alzheimer′s disease,AD)患者的神经元中,当淀粉样蛋白(β-amyloid,Aβ)和微管相关蛋白(microtubule associated protein,Tau)在线粒体中积累时,轻微损伤的线粒体通过分裂融合过程,保证部分子代线粒体内部环境的稳定,而严重损伤的子代线粒体则通过被自噬体包被,进行选择性线粒体自噬过程予以清除。当此系统功能受阻时,神经元中出现显著的线粒体运输、动力学异常等功能障碍,导致AD病理改变加重。因此,线粒体自噬在AD中扮演着重要角色。越来越多的证据提示,对线粒体自噬的调控可能为AD的治疗提供一种新方法。     

Mitophagy receptor FUNDC1 regulates mitochondrial homeostasis and protects the heart from I/R injury

Mitophagy plays pivotal roles in the selective disposal of unwanted mitochondria, and accumulation of damaged mitochondria has been linked to aging-related diseases. However, definitive proof that mitophagy regulates mitochondrial quality in vivo is lacking. It is also largely unclear whether damaged mitochondria are the cause or just the consequence of these diseases. We previously showed that FUNDC1 is a mitophagy receptor that interacts with LC3 to mediate mitophagy in response to hypoxia in cultured cells. We established Fundc1 knockout mouse models and used genetic and biochemical approaches, including a synthetic peptide that blocks the FUNDC1-LC3 interaction, to demonstrate that mitophagy regulates both mitochondrial quantity and quality in vivo in response to hypoxia or hypoxic conditions caused by ischemia-reperfusion (I/R) heart injury. We found that hypoxic mitophagy regulates platelet activities. Furthermore, we found that hypoxic preconditioning induces FUNDC1-dependent mitophagy in platelets and reduces I/R-induced heart injury, suggesting a new strategy to protect cardiac function and fight cardiovascular diseases.     

Deubiquitinating enzymes regulate PARK2-mediated mitophagy

The selective degradation of mitochondria by the process of autophagy, termed mitophagy, is one of the major mechanisms of mitochondrial quality control. The best-studied mitophagy pathway is the one mediated by PINK1 and PARK2/Parkin. From recent studies it has become clear that ubiquitin-ligation plays a pivotal role and most of the focus has been on the role of ubiquitination of mitochondrial proteins in mitophagy. Even though ubiquitination is a reversible process, very little is known about the role of deubiquitinating enzymes (DUBs) in mitophagy. Here, we report that 2 mitochondrial DUBs, USP30 and USP35, regulate PARK2-mediated mitophagy. We show that USP30 and USP35 can delay PARK2-mediated mitophagy using a quantitative mitophagy assay. Furthermore, we show that USP30 delays mitophagy by delaying PARK2 recruitment to the mitochondria during mitophagy. USP35 does not delay PARK2 recruitment, suggesting that it regulates mitophagy through an alternative mechanism. Interestingly, USP35 only associates with polarized mitochondria, and rapidly translocates to the cytosol during CCCP-induced mitophagy. It is clear that PARK2-mediated mitophagy is regulated at many steps in this important quality control pathway. Taken together, these findings demonstrate an important role of mitochondrial-associated DUBs in mitophagy. Because defects in mitochondria quality control are implicated in many neurodegenerative disorders, our study provides clear rationales for the design and development of drugs for the therapeutic treatment of neurodegenerative diseases such as Parkinson and Alzheimer diseases.     

Autosomal dominant retinitis pigmentosa-associated gene PRPF8 is essential for hypoxia-induced mitophagy through regulating ULK1 mRNA splicing

Aged and damaged mitochondria can be selectively degraded by specific autophagic elimination, termed mitophagy. Defects in mitophagy have been increasingly linked to several diseases including neurodegenerative diseases, metabolic diseases and other aging-related diseases. However, the molecular mechanisms of mitophagy are not fully understood. Here, we identify PRPF8 (pre-mRNA processing factor 8), a core component of the spliceosome, as an essential mediator in hypoxia-induced mitophagy from an RNAi screen based on a fluorescent mitophagy reporter, mt-Keima. Knockdown of PRPF8 significantly impairs mitophagosome formation and subsequent mitochondrial clearance through the aberrant mRNA splicing of ULK1, which mediates macroautophagy/autophagy initiation. Importantly, autosomal dominant retinitis pigmentosa (adRP)-associated PRPF8 mutant R2310K is defective in regulating mitophagy. Moreover, knockdown of other adRP-associated splicing factors, including PRPF6, PRPF31 and SNRNP200, also lead to ULK1 mRNA mis-splicing and mitophagy defects. Thus, these findings demonstrate that PRPF8 is essential for mitophagy and suggest that dysregulation of spliceosome-mediated mitophagy may contribute to pathogenesis of retinitis pigmentosa.     

Mitochondria removal by autophagy

Mitochondrial dysfunction has severe cellular consequences and is linked with neurodegenerative diseases and aging. Maintaining a healthy population of mitochondria is thus essential for proper cellular homeostasis. Several strategies have evolved to prevent and limit mitochondria damage, and macroautophagy plays a role in degrading superfluous or severely damaged mitochondria. Selective removal of mitochondria by autophagy (termed mitophagy) has been extensively studied recently in both yeast and mammalian cells. In this review, we summarize our current knowledge of mitophagy. We also compare the molecular process of mitophagy with other types of specific autophagic pathways and discuss its biological importance.     

SREBF1 links lipogenesis to mitophagy and sporadic Parkinson disease

Mitochondrial quality control has an impact on many diseases, but intense research has focused on the action of 2 genes linked to heritable forms of Parkinson disease (PD), PINK1 and PARK2/parkin, which act in a common pathway to promote mitophagy. However, criticism has been raised that little evidence links this mechanism to sporadic PD. To gain a greater insight into the mechanisms of PINK1-PARK2 mediated mitophagy, we undertook a genome-wide RNAi screen in Drosophila and human cell models. Strikingly, we discovered several components of the lipogenesis pathway, including SREBF1, playing a conserved role in mitophagy. Our results suggest that lipids influence the stabilization of PINK1 during the initiation of mitophagy. Importantly, SREBF1 has previously been identified as a risk locus for sporadic PD, and thus implicates aberrant mitophagy as contributing to sporadic PD. Our findings suggest a role for lipid synthesis in PINK1-PARK2 mediated mitophagy, and propose a mechanistic link between familial and sporadic PD, supporting a common etiology.     

From autophagy to mitophagy: the roles of P62 in neurodegenerative diseases

P62, also called sequestosome1 (SQSTM1), is the selective cargo receptor for autophagy to degenerate misfolded proteins. It has also been found to assist and connect parkin in pink1/parkin mitophagy pathway. Previous studies showed that p62 was in association with neurodegenerative diseases, and one of the diseases pathogenesis is P62 induced autophagy and mitophagy dysfunction. Autophagy is an important process to eliminate misfolded proteins. Intracellular aggregation including α-synuclein, Huntingtin, tau protein and ß-amyloid (Aß) protein are the misfolded proteins found in PD, HD and AD, respectively. P62 induced autophagy failure significantly accelerates misfolded protein aggregation. Mitophagy is the special autophagy, functions as the selective scavenger towards the impaired mitochondria. Mitochondrial dysfunction was confirmed greatly contribute to the occurrence of neurodegenerative diseases. Through assistance and connection with parkin, P62 is vital for regulating mitophagy, thus, aberrant P62 could influence the balance of mitophagy, and further disturb mitochondrial quality control. Therefore, accumulation of misfolded proteins leads to the aberrant P62 expression, aberrant P62 influence the balance of mitophagy, forming a vicious circle afterwards. In this review, we summarize the observations on the function of P62 relevant to autophagy and mitophagy in neurodegenerative diseases, hoping to give some clear and objective opinions to further study.     

Mitophagy: mechanisms, pathophysiological roles, and analysis

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.     

PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis

Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson disease (PD). Recent research has highlighted that two proteins encoded by genes linked to familial PD, PINK1 and parkin, play a role in the autophagic degradation of dysfunctional mitochondria (mitophagy). We have recently shown that mitochondrial dysfunction in PINK1-deficient human dopaminergic cells correlates with decreased autophagic flux and can be rescued by parkin expression. Further dissection of PINK1-parkin-dependent mitophagy indicates that the ubiquitination of mitofusins 1 and 2 is an early event. Here, we discuss how ubiquitination of the mitofusins might facilitate mitochondria degradation and the potential for activating mitophagy as a treatment for diseases affecting brain and muscle.     

SREBF1 links lipogenesis to mitophagy and sporadic Parkinson disease

Mitochondrial quality control has an impact on many diseases, but intense research has focused on the action of 2 genes linked to heritable forms of Parkinson disease (PD), PINK1 and PARK2/parkin, which act in a common pathway to promote mitophagy. However, criticism has been raised that little evidence links this mechanism to sporadic PD. To gain a greater insight into the mechanisms of PINK1-PARK2 mediated mitophagy, we undertook a genome-wide RNAi screen in Drosophila and human cell models. Strikingly, we discovered several components of the lipogenesis pathway, including SREBF1, playing a conserved role in mitophagy. Our results suggest that lipids influence the stabilization of PINK1 during the initiation of mitophagy. Importantly, SREBF1 has previously been identified as a risk locus for sporadic PD, and thus implicates aberrant mitophagy as contributing to sporadic PD. Our findings suggest a role for lipid synthesis in PINK1-PARK2 mediated mitophagy, and propose a mechanistic link between familial and sporadic PD, supporting a common etiology.