Regulation of mitochondrial dynamics and neurodegenerative diseases

Mitochondria are important cellular organelles in most metabolic processes and have a highly dynamic nature, undergoing frequent fission and fusion. The dynamic balance between fission and fusion plays critical roles in mitochondrial functions. In recent studies, several large GTPases have been identified as key molecular factors in mitochondrial fission and fusion. Moreover, the posttranslational modifications of these large GTPases, including phosphorylation, ubiquitination and SUMOylation, have been shown to be involved in the regulation of mitochondrial dynamics. Neurons are particularly sensitive and vulnerable to any abnormalities in mitochondrial dynamics, due to their large energy demand and long extended processes. Emerging evidences have thus indicated a strong linkage between mitochondria and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. In this review, we will describe the regulation of mitochondrial dynamics and its role in neurodegenerative diseases.     

The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons

PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and the exact role of this pathway in controlling mitochondrial dynamics remains controversial. Here we used mammalian primary neurons to examine the function of the PINK1/Parkin pathway in regulating mitochondrial dynamics and function. In rat hippocampal neurons, PINK1 or Parkin overexpression resulted in increased mitochondrial number, smaller mitochondrial size and reduced mitochondrial occupancy of neuronal processes, suggesting that the balance of mitochondrial fission/fusion dynamics is tipped toward more fission. Conversely, inactivation of PINK1 resulted in elongated mitochondria, indicating that the balance of mitochondrial fission/fusion dynamics is tipped toward more fusion. Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi. Functionally, PINK1 knockdown and overexpression had opposite effects on dendritic spine formation and neuronal vulnerability to excitotoxicity. Finally, we found that PINK1/Parkin similarly influenced mitochondrial dynamics in rat midbrain dopaminergic neurons. These results, together with previous findings in Drosophila dopaminergic neurons, indicate that the PINK1/Parkin pathway plays conserved roles in regulating neuronal mitochondrial dynamics and function.     

Morpho-dynamic changes of mitochondria during ageing of human endothelial cells

Mitochondrial morphology is regulated in many cultured eukaryotic cells by fusion and fission of mitochondria. A tightly controlled balance between fission and fusion events is required to ensure normal mitochondrial and cellular functions. During ageing, mitochondria are undergoing significant changes on the functional and morphological level. The effect of ageing on fusion and fission of mitochondria and consequences of altered fission and fusion activity are still unknown although theoretical models on ageing consider the significance of these processes. Human umbilical vein endothelial cells (HUVECs) have been established as a cell culture model to follow mitochondrial activity and dysfunction during the ageing process. Mitochondria of old and postmitotic HUVECs showed distinct alterations in overall morphology and fine structure, and furthermore, loss of mitochondrial membrane potential. In parallel, a decrease of intact mitochondrial DNA (mtDNA) was observed. Fission and fusion activity of mitochondria were quantified in living cells. Mitochondria of old HUVECs showed a significant and equal decrease of both fusion and fission activity indicating that these processes are sensitive to ageing and could contribute to the accumulation of damaged mitochondria during ageing.     

线粒体动力学在脓毒症心肌病中的研究进展

脓毒症心肌病为脓毒症的严重并发症之一,其确切病理机制尚不完全清楚.线粒体分裂-融合的动态过程称之为线粒体动力学,由一系列线粒体动力学相关蛋白调控.近年来,大量研究表明线粒体分裂-融合失衡可诱发各种心脏疾病,包括脓毒症心肌损害.目前对脓毒症心肌病尚无特异性治疗,心肌线粒体功能障碍与脓毒症心肌损害关系密切,调节线粒体动力学有望成为其干预的新靶点.     

The interplay between mitochondrial dynamics and mitophagy

Mitochondrial dynamics and mitophagy are recognized as two critical processes underlying mitochondrial homeostasis. Morphological and bioenergetic characterization of the life cycle of an individual mitochondrion reveals several points where fusion, fission, and mitophagy interact. Mitochondrial fission can produce an impaired daughter unit that will be targeted by the autophagic machinery. Mitochondrial fusion, on the other hand, may serve to dilute impaired respiratory components and thereby prevent their removal. The inverse dependency of fusion and mitophagy on membrane potential allows them to act as complementary rather than competitive fates of the daughter mitochondrion after a fission event. We discuss the interplay between mitochondrial dynamics and mitophagy in different tissues and in different disease models under both stress-induced and steady-state conditions.     

Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, and fatty acid metabolism has been well studied. Short-chain fatty acids (SCFAs) have been less discussed than long-chain fatty acids (LCFAs) in CVDs. However, increasing evidence indicates the importance of SCFAs in regulating cardiac function. Here, we summarize the current understanding of SCFAs in hypertension, ischaemic reperfusion, myocardial infarction, atherosclerosis and heart failure. Most SCFAs exert positive effects in regulating related diseases. Butyrate and propionate can reduce blood pressure, improve I/R injury and decrease the risk of coronary artery disease (CAD) and atherosclerosis. Acetate can also play a positive role in regulating hypertension and preventing atherosclerosis, and malonate can improve cardiac function after MI. They affect these diseases by regulating inflammation, the immune system and related G protein-coupled receptors, with multiple neurohumoural regulation participation. In contrast, succinate can accelerate IR injury, increasing mitochondrial ROS production. SCFAs ultimately affect the regulation of different pathophysiological processes in heart failure. Here, we clarified the importance of short-chain fatty acids in the cardiovascular system and their multiple effects in various pathophysiological processes, providing new insights into their promising clinical application. More research should be conducted to further elucidate the underlying mechanism and different effects of single or multiple SCFA supplementation on the cardiovascular system.     

Mitochondria as integrators of signal transduction and energy production in cardiac physiology and disease

Fascinating links are beginning to be discovered between mitochondrial function and cardiac physiology and disease in the context of diverse signaling mechanisms, energy production, and intersection with pathways producing reactive oxygen species. Proteins long known to drive mitochondrial fusion and fission are now reported to have emergent functions in intracellular calcium homeostasis, apoptosis, and vascular smooth muscle cell proliferation, all key issues in cardiac disease. Moreover, mitochondrial fusion has been demonstrated to be required for normal myofibril organization in skeletal muscle, and decreasing fission may confer protection against ischemic heart disease. These processes broaden the traditional role in energy production undertaken by mitochondria and provide new directions for potential therapeutic leads.     

线粒体功能障碍在椎间盘退变中的作用

线粒体是调节细胞功能和生存的多种细胞内信号通路的重要参与者,在年龄相关的退行性疾病中扮演了至关重要的角色.椎间盘退变是一种年龄相关的退行性疾病,以细胞外基质降解加速、细胞丢失和炎症反应为特征.近年来,大量体内外研究报道称,线粒体功能障碍通过影响多种病理生理过程,包括氧化应激、炎症小体激活、线粒体自噬、细胞衰老、细胞死亡...     

Mitochondrial fission and fusion and their roles in the heart

Mitochondria are dynamic organelles that usually exist in extensive and interconnected networks that undergo constant remodeling through fission and fusion. These processes are governed by distinct sets of proteins whose mechanism and regulation we are only beginning to fully understand. Early studies on mitochondrial dynamics were performed in yeast and simple mammalian cell culture models that allowed easy visualization of these intricate networks. Equipped with this core understanding, the field is now expanding into more complex systems. Cardiac cells are a particularly interesting example because they have unique energetic and spatial demands that make the study of their mitochondria both challenging and potentially very fruitful. This review will provide an overview of mitochondrial fission and fusion as well as recent developments in the understanding of these processes in the heart.     

线粒体的融合、分裂与炎症反应研究进展

正线粒体不仅是ATP的主要供应场所,而且参与许多细胞的信号转导过程,如Ca~(2+)内稳态、凋亡、活性氧簇(reactive oxygen species,ROS)的产生等。线粒体作为一种动态的细胞器,可以不停地进行融合与分裂运动,这种融合与分裂运动称为线粒体动力学(mitochondrial dynamics)。在正常情况下,线粒体的融合与分裂处于动态平衡状态,一旦该平衡破坏     

Role of mitochondrial quality surveillance in myocardial infarction: From bench to bedside

Myocardial infarction (MI) is the irreversible death of cardiomyocyte secondary to prolonged lack of oxygen or fresh blood supply. Historically considered as merely cardiomyocyte powerhouse that manufactures ATP and other metabolites, mitochondrion is recently being identified as a signal regulator that is implicated in the crosstalk and signal integration of cardiomyocyte contraction, metabolism, inflammation, and death. Mitochondria quality surveillance is an integrated network system modifying mitochondrial structure and function through the coordination of various processes including mitochondrial fission, fusion, biogenesis, bioenergetics, proteostasis, and degradation via mitophagy. Mitochondrial fission favors the elimination of depolarized mitochondria through mitophagy, whereas mitochondrial fusion preserves the mitochondrial network upon stress through integration of two or more small mitochondria into an interconnected phenotype. Mitochondrial biogenesis represents a regenerative program to replace old and damaged mitochondria with new and healthy ones. Mitochondrial bioenergetics is regulated by a metabolic switch between glucose and fatty acid usage, depending on oxygen availability. To maintain the diversity and function of mitochondrial proteins, a specialized protein quality control machinery regulates protein dynamics and function through the activity of chaperones and proteases, and induction of the mitochondrial unfolded protein response. In this review, we provide an overview of the molecular mechanisms governing mitochondrial quality surveillance and highlight the most recent preclinical and clinical therapeutic approaches to restore mitochondrial fitness during both MI and post-MI heart failure.     

Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion

Mitochondria are central organelles in metabolism, signal transduction, and programmed cell death. To meet their diverse functional demands, their shape is strictly regulated by a growing family of proteins that impinge on fission and fusion of the organelle. Mitochondrial fusion depends on Mitofusin (Mfn) 1 and 2, two integral outer-membrane proteins. Although MFN1 seems primarily involved in the regulation of the docking and fusion of the organelle, mounting evidence is implicating MFN2 in multiple signaling pathways not restricted to the regulation of mitochondrial shape. Here we review data supporting a role for this mitochondria-shaping protein beyond fusion, in regulating mitochondrial metabolism, apoptosis, shape of other organelles, and even progression through cell cycle. In conclusion, MFN2 appears a multifunctional protein whose biologic function is not restricted to the regulation of mitochondrial shape.     

Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission

Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTPase proteins control fusion and fission, and posttranslational modifications of these proteins are important for the regulation. However, it has not been clarified how the fusion and fission is balanced. Here, we report the molecular mechanism to regulate mitochondrial morphology in mammalian cells. Ablation of the mitochondrial fission, by repression of Drp1 or Mff, or by over‐expression of MiD49 or MiD51, results in a reduction in the fusion GTPase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA1 (L‐OPA1) in inner membrane. RNAi‐ or CRISPR‐induced ablation of Drp1 in HeLa cells enhanced the degradation of Mfns via the ubiquitin‐proteasome system (UPS). We further found that UPS‐related protein BAT3/BAG6, here we identified as Mfn2‐interacting protein, was implicated in the turnover of Mfns in the absence of mitochondrial fission. Ablation of the mitochondrial fission also enhanced the proteolytic cleavage of L‐OPA1 to soluble S‐OPA1, and the OPA1 processing was reversed by inhibition of the inner membrane protease OMA1 independent on the mitochondrial membrane potential. Our findings showed that the distinct degradation systems of the mitochondrial fusion proteins in different locations are enhanced in response to the mitochondrial morphology.     

Mitochondrial dynamics and apoptosis

In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.     

Sirtuins in mitochondrial stress: Indispensable helpers behind the scenes

Mitochondria play an essential part in guaranteeing normal cellular physiological functions through providing ATP and participating in diverse processes and signaling pathways. Recently, more and more studies have revealed the vital roles of mitochondria in coping with stressors in the aging process, metabolic disturbances and neurological disorders. Mitochondrial stress responses, including the mitochondrial unfolded protein response (UPR^mt), antioxidant defense, mitochondrial fission, mitochondrial fusion and mitophagy, are induced to maintain cellular integrity in response to stress. The sirtuin family, a group of NAD⁺-dependent deacetylases, has been the focus of much attention in recent years for their multiple regulatory functions, especially in aging and metabolism. Recent reports validated the significant link between mitochondrial stress responses and the sirtuin family, which may help to elucidate the pathogenesis and therapies for diseases such as Alzheimer’s disease or Parkinson’s disease. This review will summarize recent related studies and illuminate the interplay between sirtuins and mitochondrial stress.     

Mitochondrial function and dynamics in neural stem cells and neurogenesis: Implications for neurodegenerative diseases

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.     

Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1

Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinson's disease (PD) by inducing neurotoxicity. Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remains unclear. This study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also significantly increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). To further investigate the mechanism of SNCA's effect on mitochondrial dynamics, the proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The extracellular signal-regulated kinase (ERK) was confirmed to be involved in the regulation of DLP1 and SNCA-mediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in the future.     

慢性寒冷暴露与线粒体数量改变

目的建立慢性寒冷暴露模型,观察冷应激对线粒体数量、形态学调控蛋白及生物合成的影响并对其机制进行初步探讨。方法选取8周龄健康雄性C57BL/6J小鼠40只,随机分为对照组和寒冷组,每组各20只。寒冷组于-4~0℃环境中饲养4周建立慢性寒冷暴露模型。采用Mito Tracker在体标记小脑皮质颗粒细胞线粒体的方法统计线粒体的数量,同时应用免疫荧光染色法和Western blotting技术,检测线粒体分裂、融合蛋白及转录辅激活因子过氧化物酶体增殖活化受体γ辅助活化因子1α(PGC-1α)的表达情况。结果与对照组相比,寒冷组线粒体数量增多(P0.01),线粒体分裂、融合蛋白及转录辅激活因子PGC-1α表达均显著增多(P0.01)。结论慢性寒冷暴露可能通过诱导PGC-1α的高表达增强线粒体生物合成,增加线粒体数量;活化的PGC-1α协同冷应激促进线粒体形态学调控蛋白表达,构建新的分裂和融合的动态平衡,为机体适应低温环境提供高效率的产能机制。