Unravelling mitochondrial pathways to Parkinson's disease

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson''s disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson''s disease models. However, identification of the recessive genes implicated in Parkinson''s disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson''s disease.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

Herpesvirus Regulation of Selective Autophagy

Selective autophagy has emerged as a key mechanism of quality and quantity control responsible for the autophagic degradation of specific subcellular organelles and materials. In addition, a specific type of selective autophagy (xenophagy) is also activated as a line of defense against invading intracellular pathogens, such as viruses. However, viruses have evolved strategies to counteract the host’s antiviral defense and even to activate some proviral types of selective autophagy, such as mitophagy, for their successful infection and replication. This review discusses the current knowledge on the regulation of selective autophagy by human herpesviruses.     

BNIP3介导骨骼肌线粒体自噬：不同强度运动的影响

文题释义： BNIP3：隶属于Bcl-2蛋白超家族,是一种线粒体促凋亡蛋白,可与腺病毒转录基因E1B编码的蛋白或Bcl-2蛋白结合。可起到促进细胞凋亡、引起线粒体去极化和自噬,在机体中发挥重要作用。 线粒体自噬：线粒体是细胞的能量工厂,其功能还涉及细胞代谢、信号传导、分化、生长、凋亡和死亡等重要过程。线粒体自噬(mitophagy)是细胞清除损伤或衰老的线粒体,并循环利用其组成元素的过程;与衰老、神经退行性疾病和癌症等诸多生理病理过程密切相关。 背景：不同强度运动对机体可产生不同的影响,运动后骨骼肌的变化也不明确,而运动中机体的生理变化机制更是目前研究的热点。 目的：探讨不同强度运动对大鼠骨骼肌质量的影响以及BNIP3介导的骨骼肌线粒体自噬在维持骨骼肌质量中的作用。 方法：实验方案经北京体育大学动物实验伦理委员会批准。8周龄雄性SD大鼠24只,随机分为对照组、中等强度运动组(5°,15 m/min,1 h,60%VO_2max)和大强度运动组(5°,35 m/min,20 min,85%VO_2max),每组8只,每周运动6次。4周运动后取大鼠比目鱼肌和腓肠肌,称量湿质量,免疫荧光检测肌纤维横截面积,Western Blot检测比目鱼肌和腓肠肌BNIP3、p62和LC3蛋白的表达。 结果与结论：①腓肠肌湿质量大强度运动组和中等强度运动组显著低于对照组(P < 0.01);②比目鱼肌肌纤维横截面积大强度运动组显著小于对照组(P < 0.01);腓肠肌肌纤维横截面积中等强度运动组和大强度运动组均显著大于对照组(P < 0.01);③中等强度运动诱导线粒体自噬增加,表现为BNIP3、LC3-Ⅱ/LC3-Ⅰ值相较对照组表达增加(P < 0.05),而p62较对照组表达下降(P < 0.05);大强度运动组LC3-Ⅱ/LC3-Ⅰ、p62的表达量相较4周中等强度运动分别为上升和下降(P < 0.05),但其BNIP3的表达量却下降(P < 0.05);④结果表明,4周中等强度运动可促进骨骼肌通过BNIP3途径的线粒体自噬清除损伤线粒体,维持骨骼肌功能。4周大强度运动自噬水平更高,但可能对骨骼肌产生不利影响。 ORCID: 0000-0003-3836-3002(于亮) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Doxorubicin‐induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2

Clinical dose of doxorubicin (100 nM) induced cellular senescence and various secretory phenotypes in breast cancer and normal epithelial cells. Herein, we reported the detailed mechanism underlying ginsenoside Rh2‐mediated NF‐κB inhibition, and mitophagy promotion were evaluated by antibody array assay, western blotting analysis, and immunocytostaining. Ginsenoside Rh2 suppressed the protein levels of TRAF6, p62, phosphorylated IKK, and IκB, which consequently inactivated NF‐κB activity. Rh2‐mediated secretory phenotype was delineated by the suppressed IL‐8 secretion. Senescent epithelial cells showed increased level of reactive oxygen species (ROS), which was significantly abrogated by Rh2, with upregulation on SIRT 3 and SIRT 5 and subsequent increase in SOD1 and SOD2. Rh2 remarkably favored mitophagy by the increased expressions of PINK1 and Parkin and decreased level of PGC‐1α. A decreased secretion of IL‐8 challenged by mitophagy inhibitor Mdivi‐1 with an NF‐κB luciferase system was confirmed. Importantly, secretory senescent epithelial cells promoted the breast cancer (MCF‐7) proliferation while decreased the survival of normal epithelial cells demonstrated by co‐culture system, which was remarkably alleviated by ginsenoside Rh2 treatment. These data included ginsenoside Rh2 regulated ROS and mitochondrial autophagy, which were in large part attributed to secretory phenotype of senescent breast epithelial cells induced by doxorubicin. These findings also suggested that ginsenoside Rh2 is a potential treatment candidate for the attenuation of aging related disease.     

运动通过调控线粒体质量控制改善肌少症的研究进展

肌少症是骨骼肌质量和力量逐渐下降的过程,是老年人面临的主要健康挑战。线粒体可通过改善生物合成、抗氧化防御、融合/分裂动力学以及线粒体自噬等,维持骨骼肌自身结构和功能的完整性,线粒体功能障碍是导致肌少症的重要因素之一。运动疗法可通过激活与调控线粒体生物合成和线粒体自噬,调节线粒体质量控制,延缓和防治肌少症发生和进展。     

耐力训练对帕金森模型小鼠中脑线粒体自噬相关基因表达的影响

目的:探讨耐力训练对帕金森病(PD)模型小鼠中脑线粒体自噬的影响,揭示运动预防帕金森病的分子生物学机制。方法:10周龄雄性C57BL/6小鼠32只,随机分为安静组(C),运动组(E),帕金森模型安静组(P)及帕金森模型运动组(PE),每组8只。E组及PE组小鼠进行为期8周跑台耐力训练,跑台速度15m/min,坡度为0%,每天运动持续50min,每周6次,周日休息。训练结束后,P组和PE组小鼠腹腔注射MPTP(30mg/kg),C组和E组小鼠注射等量生理盐水,持续3d。注射结束1周后,处死各组小鼠,取双侧中脑及纹状体,采用实时PCR及Western blot技术检测线粒体自噬相关基因及TH蛋白表达,HPLC技术检测中脑及纹状体组织内DA含量。结果:与C组比,E组小鼠中脑TH蛋白上调(P0.05),中脑及纹状体DA含量均增加(P0.05),P组和PE组小鼠TH蛋白及DA含量均显著下降(P0.01),而P组较PE组相应指标下降更明显(P0.05)。与C组比,E组小鼠中脑PINK、PARK2 m RNA及PINK1蛋白表达上调(P0.05),LC3Ⅱ/Ⅰ比值增加,P组小鼠PINK1m RNA表达下调(P0.05),PE组小鼠PINK1 m RNA、Parkin蛋白含量及LC3Ⅱ/Ⅰ比值较P组增加。结论:为期3d的MPTP处理可导致小鼠中脑及纹状体TH及DA含量下降,诱导帕金森病发生,耐力训练可缓解这一现象;MPTP诱导的帕金森小鼠模型中脑线粒体自噬水平下降,而耐力训练可作用于线粒体自噬相关基因的表达,抑制MPTP的神经毒性作用。     

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy

Mitochondria as a signaling platform play crucial roles in deciding cell fate. Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage. Mitophagy, one selective autophagy, is the key mitochondrial quality control that effectively removes damaged mitochondria. However, the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear. Here, we examined the functional implication of mitophagy in the anticancer properties of magnolol, a natural product isolated from herbal Magnolia officinalis. First, we found that magnolol induces mitochondrial depolarization, causes excessive mitochondrial fragmentation, and increases mitochondrial reactive oxygen species (mtROS). Second, magnolol induces PTEN-induced putative kinase protein 1 (PINK1)‒Parkin-mediated mitophagy through regulating two positive feedforward amplification loops. Third, magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway. Moreover, magnolol prolongs the survival time of tumor-bearing mice. Finally, inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy, both in vitro and in vivo. Altogether, our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis, whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol, suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.     

线粒体自噬的调控机制及其在脑缺血再灌注损伤中的作用

自噬作为参与细胞代谢和细胞器更新的调节机制,在机体的生理和病理过程中扮演着重要的角色.线粒体自噬作为细胞靶物特异性自噬的一种,可识别和清除功能受损的线粒体,实现线粒体的质量控制.线粒体主要通过Parkin依赖途径和非Parkin依赖途径调节自噬,从而影响机体的机能.研究表明线粒体自噬与脑缺血再灌注损伤过程有密切的关系,...     

线粒体自噬信号通路在年龄相关性眼病中的研究进展

线粒体自噬是一种特殊形式的自噬,通过选择性清除功能失调和多余的线粒体,从而为细胞产生能量并调节能量稳态。同时,线粒体自噬具有促进细胞分化和延缓衰老等生理功能,其调控机制一旦失调或出现障碍将会导致生理性衰老和一系列与年龄相关的疾病发生。有研究发现,在多种年龄相关性眼病中存在着不同水平的线粒体自噬,如Fuchs内皮角膜营养不良、老年性白内障和原发性开角型青光眼等。本综述旨在概述线粒体自噬的相关信号通路及线粒体自噬在年龄相关性眼病中的研究进展。