All the little pieces. -Regulation of mitochondrial fusion and fission by ubiquitin and small ubiquitin-like modifer and their potential relevance in the heart.-

Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.     

Mitochondrial biogenesis and healthy aging

Aging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan. Mitochondria are particularly susceptive to damage over time as they are the major bioenergetic machinery and source of oxidative stress in cells. Effective control of mitochondrial biogenesis and turnover, therefore, becomes critical for the maintenance of energy production, the prevention of endogenous oxidative stress and the promotion of healthy aging. Multiple endogenous and exogenous factors regulate mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Activators of PGC-1alpha include nitric oxide, CREB and AMPK. Calorie restriction (CR) and resveratrol, a proposed CR mimetic, also increase mitochondrial biogenesis through activation of PGC-1alpha. Moderate exercise also mimics CR by inducing mitochondrial biogenesis. Negative regulators of PGC-1alpha such as RIP140 and 160MBP suppress mitochondrial biogenesis. Another mechanism involved in mitochondrial maintenance is mitochondrial fission/fusion and this process also involves an increasing number of regulatory proteins. Dysfunction of either biogenesis or fission/fusion of mitochondria is associated with diseases of the neuromuscular system and aging, and a greater understanding of the regulation of these processes should help us to ultimately control the aging process.     

Evolution of the mitochondrial fusion-fission cycle and its role in aging

Mitochondria are organelles of eukaryotic cells that contain their own genetic material and evolved from prokaryotic ancestors some 2 billion years ago. They are the main source of the cell's energy supply and are involved in such important processes as apoptosis, mitochondrial diseases, and aging. During recent years it also became apparent that mitochondria display a complex dynamical behavior of fission and fusion, the function of which is as yet unknown. In this paper we develop a concise theory that explains why fusion and fission have evolved, how these processes are related to the accumulation of mitochondrial mutants during aging, why the mitochondrial DNA has to be located close to the respiration complexes where most radicals are generated, and what selection pressures shaped the slightly different structure of animal and plant mitochondria. We believe that this "organelle control" theory will help in understanding key processes involved in the evolution of the mitochondrial genome and the aging process.     

Mitochondria in heart failure: the emerging role of mitochondrial dynamics

Over the past decade, mitochondria have emerged as critical integrators of energy production, generation of reactive oxygen species (ROS), multiple cell death, and signaling pathways in the constantly beating heart. Clarification of the molecular mechanisms, underlying mitochondrial ROS generation and ROS-induced cell death pathways, associated with cardiovascular diseases, by itself remains an important aim; more recently, mitochondrial dynamics has emerged as an important active mechanism to maintain normal mitochondria number and morphology, both are necessary to preserve cardiomyocytes integrity. The two opposing processes, division (fission) and fusion, determine the cell type-specific mitochondrial morphology, the intracellular distribution and activity. The tightly controlled balance between fusion and fission is of particular importance in the high energy demanding cells, such as cardiomyocytes, skeletal muscles, and neuronal cells. A shift toward fission will lead to mitochondrial fragmentation, observed in quiescent cells, while a shift toward fusion will result in the formation of large mitochondrial networks, found in metabolically active cardiomyocytes. Defects in mitochondrial dynamics have been associated with various human disorders, including heart failure, ischemia reperfusion injury, diabetes, and aging. Despite significant progress in our understanding of the molecular mechanisms of mitochondrial function in the heart, further focused research is needed to translate this knowledge into the development of new therapies for various ailments.     

Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system

Mitochondria are essential organelles that produce the cellular energy source, ATP. Dysfunctional mitochondria are involved in the pathophysiology of heart disease, which is associated with reduced levels of ATP and excessive production of reactive oxygen species. Mitochondria are dynamic organelles that change their morphology through fission and fusion in order to maintain their function. Fusion connects neighboring depolarized mitochondria and mixes their contents to maintain membrane potential. In contrast, fission segregates damaged mitochondria from intact ones, where the damaged part of mitochondria is subjected to mitophagy whereas the intact part to fusion. It is generally believed that mitochondrial fusion is beneficial for the heart, especially under stress conditions, because it consolidates the mitochondria's ability to supply energy. However, both excessive fusion and insufficient fission disrupt the mitochondrial quality control mechanism and potentiate cell death. In this review, we discuss the role of mitochondrial dynamics and mitophagy in the heart and the cardiomyocytes therein, with a focus on their roles in cardiovascular disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".     

Regulatory role of mitochondria in oxidative stress and atherosclerosis

Mitochondrial physiology and biogenesis play a crucial role in the initiation and progression of cardiovascular disease following oxidative stress-induced damage such as atherosclerosis (AST). Dysfunctional mitochondria caused by an increase in mitochondrial reactive oxygen species (ROS) production, accumulation of mitochondrial DNA damage, and respiratory chain deficiency induces death of endothelial/smooth muscle cells and favors plaque formation/rupture via the regulation of mitochondrial biogenesis-related genes such as peroxisome proliferator-activated receptor γ coactivator (PGC-1), although more detailed mechanisms still need further study. Based on the effect of healthy mitochondria produced by mitochondrial biogenesis on decreasing ROS-mediated cell death and the recent finding that the regulation of PGC-1 involves mitochondrial fusion-related protein (mitofusin), we thus infer the regulatory role of mitochondrial fusion/fission balance in AST pathophysiology. In this review, the first section discusses the possible association between AST-inducing factors and the molecular regulatory mechanisms of mitochondrial biogenesis and dynamics, and explains the role of mitochondria-dependent regulation in cell apoptosis during AST development. Furthermore, nitric oxide has the Janus-faced effect by protecting vascular damage caused by AST while being a reactive nitrogen species (RNS) which act together with ROS to damage cells. Therefore, in the second section we discuss mitochondrial ATP-sensitive K(+) channels, which regulate mitochondrial ion transport to maintain mitochondrial physiology, involved in the regulation of ROS/RNS production and their influence on AST/cardiovascular diseases (CVD). Through this review, we can further appreciate the multi-regulatory functions of the mitochondria involved in AST development. The understanding of these related mechanisms will benefit drug development in treating AST/CVD through targeted biofunctions of mitochondria.     

Mitochondrial dynamics and cell death in heart failure

The highly regulated processes of mitochondrial fusion (joining), fission (division) and trafficking, collectively called mitochondrial dynamics, determine cell-type specific morphology, intracellular distribution and activity of these critical organelles. Mitochondria are critical for cardiac function, while their structural and functional abnormalities contribute to several common cardiovascular diseases, including heart failure (HF). The tightly balanced mitochondrial fusion and fission determine number, morphology and activity of these multifunctional organelles. Although the intracellular architecture of mature cardiomyocytes greatly restricts mitochondrial dynamics, this process occurs in the adult human heart. Fusion and fission modulate multiple mitochondrial functions, ranging from energy and reactive oxygen species production to Ca²⁺ homeostasis and cell death, allowing the heart to respond properly to body demands. Tightly controlled balance between fusion and fission is of utmost importance in the high energy-demanding cardiomyocytes. A shift toward fission leads to mitochondrial fragmentation, while a shift toward fusion results in the formation of enlarged mitochondria and in the fusion of damaged mitochondria with healthy organelles. Mfn1, Mfn2 and OPA1 constitute the core machinery promoting mitochondrial fusion, whereas Drp1, Fis1, Mff and MiD49/51 are the core components of fission machinery. Growing evidence suggests that fusion/fission factors in adult cardiomyocytes play essential noncanonical roles in cardiac development, Ca²⁺ signaling, mitochondrial quality control and cell death. Impairment of this complex circuit causes cardiomyocyte dysfunction and death contributing to heart injury culminating in HF. Pharmacological targeting of components of this intricate network may be a novel therapeutic modality for HF treatment.     

Morphological dynamics of mitochondria — A special emphasis on cardiac muscle cells

Mitochondria play a critical role in cellular energy metabolism, Ca²⁺ homeostasis, reactive oxygen species generation, apoptosis, aging, and development. Many recent publications have shown that a continuous balance of fusion and fission of these organelles is important in maintaining their proper function. Therefore, there is a steep correlation between the form and function of mitochondria. Many major proteins involved in mitochondrial fusion and fission have been identified in different cell types, including heart. However, the functional role of mitochondrial dynamics in the heart remains, for the most part, unexplored. In this review we will cover the recent field of mitochondrial dynamics and its physiological and pathological implications, with a particular emphasis on the experimental and theoretical basis of mitochondrial dynamics in the heart.     

Integrity of the yeast mitochondrial genome,but not its distribution and inheritance,relies on mitochondrial fission and fusion

Mitochondrial DNA (mtDNA) is essential for mitochondrial and cellular function. In Saccharomyces cerevisiae, mtDNA is organized in nucleoprotein structures termed nucleoids, which are distributed throughout the mitochondrial network and are faithfully inherited during the cell cycle. How the cell distributes and inherits mtDNA is incompletely understood although an involvement of mitochondrial fission and fusion has been suggested. We developed a LacO-LacI system to noninvasively image mtDNA dynamics in living cells. Using this system, we found that nucleoids are nonrandomly spaced within the mitochondrial network and observed the spatiotemporal events involved in mtDNA inheritance. Surprisingly, cells deficient in mitochondrial fusion and fission distributed and inherited mtDNA normally, pointing to alternative pathways involved in these processes. We identified such a mechanism, where we observed fission-independent, but F-actin–dependent, tip generation that was linked to the positioning of mtDNA to the newly generated tip. Although mitochondrial fusion and fission were dispensable for mtDNA distribution and inheritance, we show through a combination of genetics and next-generation sequencing that their absence leads to an accumulation of mitochondrial genomes harboring deleterious structural variations that cluster at the origins of mtDNA replication, thus revealing crucial roles for mitochondrial fusion and fission in maintaining the integrity of the mitochondrial genome.Mitochondrial DNA (mtDNA) is essential for respiratory growth of all eukaryotic cells, and all multicellular organisms depend on mtDNA for their development. Not surprisingly, given the fundamental importance of mtDNA, mutations within mtDNA have been identified as the cause for a plethora of human diseases (1). mtDNA in Saccharomyces cerevisiae encodes for seven essential subunits of the respiratory chain, one protein and two RNA subunits of the mitochondrial ribosome, 24 tRNAs, and the RNA subunit of RNase P (2). Every cell contains 50–100 copies of mtDNA that are organized into nucleoprotein complexes termed nucleoids, each containing 1–10 copies of mtDNA (3, 4). Nucleoids are distributed throughout the mitochondrial network, which is likely important for equivalently supplying spatially separated mitochondrial segments with mitochondrially encoded proteins.How the distribution of mtDNA throughout the mitochondrial network is established and maintained is not fully understood. Previous work from our laboratory and others has shown that the movement of nucleoids within the mitochondrial network is limited, suggesting that the mechanisms of nucleoid distribution are tightly interlinked with the dynamics of mitochondria themselves (5, 6). Mitochondria undergo constant fusion and fission events that are mediated by dedicated machineries, with the central components Fzo1 and Dnm1 required for fusion and fission, respectively (7). Recently, we have provided support for a role of mitochondrial fission in mtDNA distribution. We have shown that mtDNA localizes to sites of Dnm1-dependent mitochondrial fission and that it is segregated after scission to both of the newly generated mitochondrial tips (8). Localizing mtDNA to the newly formed tips would then allow transport of mitochondrial tips and mtDNA to distal parts in the cell, where fusion with the mitochondrial network may drive mtDNA distribution. Such a mechanism would be particularly important during inheritance of mtDNA to daughter buds during cell division, where mtDNA needs to be transported over a relatively large distance. In S. cerevisiae, mitochondria are inherited in a myosin- and F-actin–dependent process, in which a mitochondrial tubule invades the budding daughter cell and is subsequently anchored at the distal membrane (9). An active mtDNA partition and inheritance apparatus has been postulated (6); however, the spatiotemporal relationship between the inheritance of mitochondria and the inheritance of mtDNA has not been examined.If mitochondrial fusion and fission were essential for the distribution and inheritance of mtDNA, their loss would impair the process. Indeed, fusion-defective cells lose mtDNA (10, 11), most likely due to excessive fragmentation. By contrast, however, fission-defective cells, as well as cells defective in fusion and fission, remain capable of respiratory growth, indicating that a functional mitochondrial genome must be maintained (10, 12). These observations suggest that fission-independent mechanisms must exist that facilitate mtDNA inheritance.In this work, we investigated the role of mitochondrial fusion and fission in mtDNA distribution and inheritance. Through the development of a noninvasive method to quantify the spatial organization of mtDNA within mitochondrial tubules, we found that cells deficient in fusion and fission maintain a WT distribution of mtDNA. Live-cell imaging showed that this distribution is facilitated by the de novo generation of tubules from the sides of existing tubules, a process coupled to the spatial positioning of mtDNA to the newly formed tip. Unexpectedly, although dispensable for maintaining mtDNA distribution and inheritance, fusion and fission were required to maintain the integrity of the mitochondrial genome.     

mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca(2+), and lipid insults in NARP cybrids: a potential therapeutic target for melatonin

Mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. This study investigated how mtDNA T8993G (NARP)-induced inhibition of mitochondrial complex V altered mitochondrial dynamics in association with a protective mitochondrial phospholipid, cardiolipin (CL), as a potential therapeutic target. NARP cybrids harboring 98% of mtDNA T8993G genes and its parental osteosarcoma 143B cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. We demonstrate for the first time that NARP mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxidative, Ca(2+), and lipid stress. In addition, NARP significantly augmented pathological depletion of CL. NARP-augmented depletion of CL results in enhanced retardation of mitochondrial movement and fission and later swelling of mitochondria during all insults. These results suggest that CL is a common and crucial pathological target for mitochondrial apoptotic insults. Furthermore, CL possibly plays a central role in regulating mitochondrial dynamics that are associated with NARP-augmented mitochondrial pathologies. Intriguingly, melatonin, by differentially preserving CL during various stresses (oxidation > Ca(2+) > lipid), rescues differentially CL-altered mitochondrial dynamics and cell death (oxidation > Ca(2+) > lipid). Thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability transition modulator to antagonize mitochondrial Ca(2+) stress, may stabilize directly CL to prevent its oxidization and/or depletion and, therefore, exerts great potential in rescuing CL-dependent mitochondrial dynamics-associated mitochondrial pathologies for treatment of NARP-induced pathologies and diseases.     

Mitochondrial repair of 8-oxoguanine and changes with aging

Reactive oxygen species (ROS) are formed in all living organisms as a by-product of normal metabolism (endogenous sources) and as a consequence of exposure to environmental compounds (exogenous sources). Endogenous ROS are largely formed during oxidative phosphorylation in the mitochondria and, therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Mitochondria are essential for cell viability, and oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. One of the most common oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which can introduce G/C to T/A transversions after DNA replication. Oxidative DNA base lesions, including 8-oxoG, are repaired primarily by the base excision repair (BER) pathway. While we know much about how this pathway functions in processing the nuclear DNA lesions, little is yet known about BER in mitochondria. We have used a number of different approaches to explore the mechanisms of DNA damage processing in the mtDNA. We have been able to demonstrate that mammalian mitochondria efficiently remove 8-oxoG from their genome, and that the efficiency of 8-oxoG incision increases with age in rats and mice. Yet 8-oxoG accumulates in mtDNA during aging. Changes in mitochondrial function with age have been observed in several organisms and accumulation of DNA lesions in mtDNA with age may be an underlying cause for numerous age-associated diseases including cancer.     

Mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes?

Mitochondria are key in the metabolism of aerobic organisms and in ageing progression and age-related diseases. Mitochondria are essential for obtaining ATP from glucose and fatty acids but also in many other essential functions in cells including aminoacids metabolism, pyridine synthesis, phospholipid modifications and calcium regulation. On the other hand, the activity of mitochondria is also the principal source of reactive oxygen species in cells. Ageing and chronic age-related diseases are associated with the deregulation of cell metabolism and dysfunction of mitochondria. Cell metabolism is controlled by three major nutritional sensors: mTOR, AMPK and Sirtuins. These factors control mitochondrial biogenesis and dynamics by regulating fusion, fission and turnover through mito- and autophagy. A complex interaction between the activity of these nutritional sensors, mitochondrial biogenesis rate and dynamics exists and affect ageing, age-related diseases including metabolic disease. Further, mitochondria maintain a constant communication with nucleus modulating gene expression and modifying epigenetics. In this review we highlight the importance of mitochondria in ageing and the repercussion in the progression of age-related diseases and metabolic disease.     

Mitochondrial dynamics in heart failure

Mitochondria have been widely studied for their critical role in cellular metabolism, energy production, and cell death. New developments in research on mitochondria derived from studies in yeast have led to the discovery of entirely new mitochondrial processes that have implications for mitochondrial function in heart failure. Recent studies have identified that maintaining normal mitochondrial morphology and function depends on the dynamic balance of mitochondrial fusion and fission (division). Mitochondrial fusion and fission are constant ongoing processes, which are essential for the maintenance of normal mitochondrial function. Studies in heart failure have been limited but suggest a possible reduction in mitochondrial fusion. As mitochondrial fusion and fission have important links to apoptosis, a key mechanism of loss of cardiac myocytes in heart failure, there are many implications for both heart failure research and treatment.     

Frequent fusion and fission of plant mitochondria with unequal nucleoid distribution

The balance between mitochondrial fusion and fission influences the reticular shape of mitochondria in yeasts. Little is known about whether mitochondria fusion occurs in plants. Plant mitochondria are usually more numerous and more grain-shaped than animal mitochondria. BLAST searches of the nuclear and mitochondrial genome sequences of Arabidopsis thaliana did not find any obvious homologue of mitochondrial fusion genes found in animals and yeasts. To determine whether mitochondrial fusion actually occurs in plants, we labeled mitochondria in onion epidermal cells with a mitochondria-targeted, photoconvertible fluorescent protein Kaede and then altered the fluorescence of some of the mitochondria within a cell from green to red. Frequent and transient fusion of red and green mitochondria was demonstrated by the appearance of yellow mitochondria that subsequently redivided. We also show that mitochondrial fission occasionally occurs without an equal distribution of the nucleoid (DNA-protein complex in mitochondria), resulting in the coexistence of mitochondria containing various amounts of DNA within a single cell. The heterogeneity of DNA contents in mitochondria may be overcome by the frequent and transient fusion of mitochondria.     

Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology

Remodeling of mitochondria is a dynamic process coordinated by fusion and fission of the inner and outer membranes of the organelle, mediated by a set of conserved proteins. In metazoans, the molecular mechanism behind mitochondrial morphology has been recruited to govern novel functions, such as development, calcium signaling, and apoptosis, which suggests that novel mechanisms should exist to regulate the conserved membrane fusion/fission machinery. Here we show that phosphorylation and cleavage of the vertebrate-specific Pbeta domain of the mammalian presenilin-associated rhomboid-like (PARL) protease can influence mitochondrial morphology. Phosphorylation of three residues embedded in this domain, Ser-65, Thr-69, and Ser-70, impair a cleavage at position Ser(77)-Ala(78) that is required to initiate PARL-induced mitochondrial fragmentation. Our findings reveal that PARL phosphorylation and cleavage impact mitochondrial dynamics, providing a blueprint to study the molecular evolution of mitochondrial morphology.     

线粒体融合蛋白2在心血管疾病中的研究现状

线粒体是一个处于不断地融合与分裂过程中的动态细胞器。线粒体融合蛋白2(Mfn2)作为广泛分布于线粒体外膜和线粒体结合内质网膜上具有多重功能的蛋白,参与维持正常细胞功能。除了参与线粒体融合外,Mfn2还能够调节线粒体代谢、促进损伤线粒体的自噬、增强线粒体与内质网交流、维持内质网功能及通过调控线粒体外膜通透性和渗透性钙转运孔道的启闭参与细胞死亡过程等。另外,Mfn2基因还可通过调控Ras-Raf-ERK/MAPK和Ras-PI3K-Akt信号通路分别参与调控血管平滑肌细胞的增殖和凋亡过程。Mfn2的这一系列重要的生物学功能有助于其参与高血压、肺动脉高压、动脉粥样硬化、急性缺血/再灌损伤、扩张性心肌病、心肌肥大、心衰和肥胖糖尿病等多种心血管疾病的发生发展过程。研究Mfn2与心血管疾病的相关性也许能为临床提供一个心血管疾病潜在治疗的靶点。因此,本文将综述Mfn2在心血管疾病相关研究中的现状。     

Mitochondrial biogenesis and fragmentation as regulators of protein degradation in striated muscles

Mitochondria are dynamic organelles which adapt their morphology by fusion and fission events to the bioenergetic requirements of the cell. Cardiac and skeletal muscles are tissues with high energy demand and mitochondrial plasticity plays a key role in the homeostasis of these cells. Indeed, alterations in mitochondrial morphology, distribution and function are common features in catabolic conditions. Moreover, dysregulation of mitochondrial dynamics affects the signaling pathways that regulate muscle mass. This review discusses the recent findings of the role of mitochondrial fusion/fission and mitophagy in the control of proteolytic pathways. This article is part of a special issue entitled "Focus on Cardiac Metabolism".     

Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery

Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.     

Mitochondrial diabetes mellitus

This review discusses the current insight by which mutations in mitochondrial DNA (mtDNA) contribute to the development of particular disease states with emphasis on diabetes mellitus. Mitochondria are the power factories of the cells and produce ATP by oxidizing reducing equivalents via the respiratory chain. These reducing equivalents originate mainly from the citric acid cycle that also occurs within the mitochondria. Human mitochondria contain their own genetic material in the form of circular DNA that encodes for only a fraction of the mitochondrial components. The other mitochondrial components are nuclear encoded. Pathogenic mutations in mtDNA can affect the activity of the respiratory chain, thereby leading to the reduced generation of ATP. However, mitochondria not only produce ATP but they also regulate cytosolic concentrations of signaling molecules such as calcium and iron ions. The metabolic processes within mitochondria such as the citric acid cycle determine the concentration of metabolites that can also act as signalling molecules. Furthermore, the respiratory chain and mitochondrion-associated monoamine oxidase are major producers of reactive oxygen radicals. As a result, mutations in mtDNA can deregulate multiple processes within cells and the balance of this deregulation may contribute to the clinical phenotype.