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1.  After the banquet 
Autophagy  2013;9(11):1663-1676.
Mitochondria are highly dynamic organelles of crucial importance to the proper functioning of neuronal, cardiac and other cell types dependent upon aerobic efficiency. Mitochondrial dysfunction has been implicated in numerous human conditions, to include cancer, metabolic diseases, neurodegeneration, diabetes, and aging. In recent years, mitochondrial turnover by macroautophagy (mitophagy) has captured the limelight, due in part to discoveries that genes linked to Parkinson disease regulate this quality control process. A rapidly growing literature is clarifying effector mechanisms that underlie the process of mitophagy; however, factors that regulate positive or negative cellular outcomes have been less studied. Here, we review the literature on two major pathways that together may determine cellular adaptation vs. cell death in response to mitochondrial dysfunction. Mitochondrial biogenesis and mitophagy represent two opposing, but coordinated processes that determine mitochondrial content, structure, and function. Recent data indicate that the capacity to undergo mitochondrial biogenesis, which is dysregulated in disease states, may play a key role in determining cell survival following mitophagy-inducing injuries. The current literature on major pathways that regulate mitophagy and mitochondrial biogenesis is summarized, and mechanisms by which the interplay of these two processes may determine cell fate are discussed. We conclude that in primary neurons and other mitochondrially dependent cells, disruptions in any phase of the mitochondrial recycling process can contribute to cellular dysfunction and disease. Given the emerging importance of crosstalk among regulators of mitochondrial function, autophagy, and biogenesis, signaling pathways that coordinate these processes may contribute to therapeutic strategies that target or regulate mitochondrial turnover and regeneration.
PMCID: PMC4028332  PMID: 23787782
mitophagy; cell death; mitochondrial biogenesis; LC3 interacting proteins; parkin; PINK1; AMPK; PGC-1alpha; extracellular signal regulated protein kinase (ERK1/2)
2.  Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis 
PLoS Pathogens  2013;9(12):e1003722.
Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.
Author Summary
Hepatitis B virus (HBV) chronic infections represent the common cause for the development of hepatocellular carcinoma. Mitochondrial liver injury has been long recognized as one of the consequences of HBV infection during chronic hepatitis. Mitochondria are dynamic organelles that undergo fission, fusion, and selective-autophagic removal (mitophagy), in their pursuit to maintain mitochondrial homeostasis and meet cellular energy requirements. The clearance of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. We observed that HBV and its encoded HBx protein promoted mitochondrial fragmentation (fission) and mitophagy. HBV/HBx induced the expression and Ser616 phosphorylation of dynamin-related protein 1 (Drp1) and its subsequent translocation to the mitochondria, resulting in enhanced mitochondrial fragmentation. HBV also promoted the mitochondrial translocation of Parkin, a cytosolic E3 ubiquitin ligase, and subsequent mitophagy. Perturbation of mitophagy in HBV-infected cells resulted in enhanced mitochondrial apoptotic signaling. This shift of the mitochondrial dynamics towards enhanced fission and mitophagy is essential for the clearance of damaged mitochondria and serves to prevent apoptotic cell death of HBV-infected cells to facilitate persistent infection.
PMCID: PMC3855539  PMID: 24339771
3.  Redox Regulation of Mitochondrial Function 
Antioxidants & Redox Signaling  2012;16(11):1323-1367.
Redox-dependent processes influence most cellular functions, such as differentiation, proliferation, and apoptosis. Mitochondria are at the center of these processes, as mitochondria both generate reactive oxygen species (ROS) that drive redox-sensitive events and respond to ROS-mediated changes in the cellular redox state. In this review, we examine the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux. In particular, we focus on the actions of redox-sensitive targets that alter mitochondrial function and the role of these redox modifications on metabolism, mitochondrial biogenesis, receptor-mediated signaling, and apoptotic pathways. We also consider the role of mitochondria in modulating these pathways, and discuss how redox-dependent events may contribute to pathobiology by altering mitochondrial function. Antioxid. Redox Signal. 16, 1323–1367.
I. Introduction
II. Cellular ROS, Redox, and Antioxidant Systems
A. Sources of cellular ROS
B. Mitochondrial generation of ROS
C. Redox and antioxidant systems
1. SODs
2. Catalase and NADPH
3. GPx, reduced glutathione, Grxs, and glutathione reductase
4. Prxs, Trx, and TrxR
5. Cytosolic and mitochondrial NADPH
D. Redox-active Cys
1. Cys oxidation states and functional modification of protein thiols
2. Protein S-glutathiolation
3. Protein S-nitrosation
4. Mitochondrial function and the thiol redox state
5. Mitochondrial disulfide-relay system
E. Metabolism, NADH/NAD+, and NADPH/NADP+
1. Regulation of glycolysis
2. SIRT, NAD+, and metabolic regulation
III. Functional Consequences of Redox Modifiers
A. NO·
1. Apoptosis and NO·
2. NO· and mitochondrial fission and fusion
3. NO· and mitochondrial respiration
B. Reactive oxygen species
1. NADPH activation of mitochondrial ROS
2. Other ROS-mediated ROS generators
3. Extracellular redox state and mitochondrial function
4. Mitochondrial ROS and receptor-mediated signaling
5. Mitochondrial respiration, inner mitochondrial membrane potential, and ROS
6. UCPs and mitochondrial function
IV. Redox Regulation of Mitochondrial Turnover
A. Mitochondrial biogenesis
1. Overview of biogenesis
2. ROS and biogenesis
3. Telomere dysfunction and mitochondrial biogenesis
B. ROS and mitophagy versus apoptosis
C. Heme oxygenase, carbon monoxide, and mitochondrial function
V. Redox Regulation of Apoptosis
A. ASK1 and Trx-mediated regulation of JNK
B. MPT pore and cell death
1. Mitochondrial permeability transition
2. Mitochondrial Ca2+, redox, and mitochondrial dysfunction
3. STAT3 and mitochondrial function
C. Lipid oxidation and apoptotic signaling
1. Cardiolipin oxidation and apoptosis
2. Membrane phospholipids and AIF-mediated cell death
VI. Mitochondrial Responses to Hypoxia
VII. Conclusion
PMCID: PMC3324814  PMID: 22146081
4.  Dysregulation of Mfn2 and Drp-1 proteins in heart failure1 
Therapeutic approaches for cardiac regenerative mechanisms have been explored over the past decade to target various cardiovascular diseases (CVD). Structural and functional aberrations of mitochondria have been observed in CVD. The significance of mitochondrial maturation and function in cardiomyocytes is distinguished by their attribution to embryonic stem cell differentiation into adult cardiomyocytes. An abnormal fission process has been implicated in heart failure, and treatment with mitochondrial division inhibitor 1 (Mdivi-1), a specific inhibitor of dynamin related protein-1 (Drp-1), has been shown to improve cardiac function. We recently observed that the ratio of mitofusin 2 (Mfn2; a fusion protein) and Drp-1 (a fission protein) was decreased during heart failure, suggesting increased mitophagy. Treatment with Mdivi-1 improved cardiac function by normalizing this ratio. Aberrant mitophagy and enhanced oxidative stress in the mitochondria contribute to abnormal activation of MMP-9, leading to degradation of the important gap junction protein connexin-43 (Cx-43) in the ventricular myocardium. Reduced Cx-43 levels were associated with increased fibrosis and ventricular dysfunction in heart failure. Treatment with Mdivi-1 restored MMP-9 and Cx-43 expression towards normal. In this review, we discuss mitochondrial dynamics, its relation to MMP-9 and Cx-43, and the therapeutic role of fission inhibition in heart failure.
PMCID: PMC4228691  PMID: 24905188
mitochondrial fission; fusion; Drp-1; Mfn2; Cx-43; MMP-9; pressure overload heart failure
5.  Potential Therapeutic Benefits of Strategies Directed to Mitochondria 
Antioxidants & Redox Signaling  2010;13(3):279-347.
The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347.
Introduction and Topics Reviewed
Anatomy and Function of Mitochondrial Membranes
Outer mitochondrial membrane and its potential role as therapeutic target
Inner mitochondrial membrane and its potential role as therapeutic target
Mitochondrial permeability transition pore
Electron Transport Chain and Oxidative Phosphorylation: Modulation by Mitochondrial Ion Channels and Exchangers
Mitochondrial ROS and RNS
Mitochondria and reactive oxygen species
Mitochondria and reactive nitrogen species
Mitochondrial ROS Scavenging and Its Potential Therapeutic Value
Manganese superoxide dismutase
Glutathione thioredoxin, and peroxiredoxin systems
Catalase and glutathione peroxidase
Cytochrome c
Mitochondria as scavengers of cytosolic O2•−
Uncoupling Proteins in Modulation of Mitochondrial Function: Physiological and Pharmacologic Relevance
Mitochondrial DNA-Related Pathologies and a Potential Therapeutic Target
Mitochondrial Interaction with other Organelles: Therapeutic Implications
Mitochondrion—mitochondrion interaction
Mitochondrion—nucleus interaction
Mitochondria—endoplasmic/sarcoplasmic reticulum interaction
Mitochondria-Related Diseases and Cell Injury
Mitochondria and cardiac ischemia and reperfusion injury
Mitochondria and the failing heart
Mitochondria and diabetes
Mitochondria and hypertension
Mitochondria and neurodegenerative diseases
Alzheimer's disease
Parkinson's disease
Amyotrophic lateral sclerosis
Friedreich's ataxia
Neoplastic diseases
Other mitochondria-related diseases
Mitochondria and psychiatric disorders
Mitochondria and migraine headache
Mitochondrial Pharmacology and Therapeutic Potential
Strategies for drug delivery to mitochondria
Mitochondria-targeted drugs
Approaches to improve mitochondrial function during ischemia and reperfusion
Other Mitochondrial Therapeutic Approaches
Lipid replacement therapy
Transactivator of transcription proteins and mitochondrial therapy
Molecular genetics approaches
Mitochondria and caloric restriction
Mitochondria and dietary supplements
Mitochondria Age and Lifespan
Mitochondria and age-associated diseases
Mitochondrial p66shc and lifespan
Caveats and Potential Limitations in Mitochondrial Drug Targeting
Conclusion and Perspectives
PMCID: PMC2936955  PMID: 20001744
6.  Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? 
Mitochondrial dynamics is a recent topic of research in the field of cardiac physiology. The study of mechanisms involved in the morphological changes and in the mobility of mitochondria is legitimate since the adult cardiomyocytes possess numerous mitochondria which occupy at least 30% of cell volume. However, architectural constraints exist in the cardiomyocyte that limit mitochondrial movements and communication between adjacent mitochondria. Still, the proteins involved in mitochondrial fusion and fission are highly expressed in these cells and could be involved in different processes important for the cardiac function. For example, they are required for mitochondrial biogenesis to synthesize new mitochondria and for the quality-control of the organelles. They are also involved in inner membrane organization and may play a role in apoptosis. More generally, change in mitochondrial morphology can have consequences in the functioning of the respiratory chain, in the regulation of the mitochondrial permeability transition pore (MPTP), and in the interactions with other organelles. Furthermore, the proteins involved in fusion and fission of mitochondria are altered in cardiac pathologies such as ischemia/reperfusion or heart failure (HF), and appear to be valuable targets for pharmacological therapies. Thus, mitochondrial dynamics deserves particular attention in cardiac research. The present review draws up a report of our knowledge on these phenomena.
PMCID: PMC3650619  PMID: 23675354
mitochondrial dynamics; cardiomyocytes; adult; energetic metabolism; cytoarchitecture
7.  New Insights into the Role of Mitochondrial Dynamics and Autophagy during Oxidative Stress and Aging in the Heart 
The heart is highly sensitive to the aging process. In the elderly, the heart tends to become hypertrophic and fibrotic. Stiffness increases with ensuing systolic and diastolic dysfunction. Aging also affects the cardiac response to stress. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. The accumulation of dysfunctional and abnormal mitochondria is an important pathophysiological feature of the aging process, which is associated with excessive production of reactive oxygen species. Mitochondrial fusion and fission and mitochondrial autophagy are crucial mechanisms for maintaining mitochondrial function and preserving energy production. In particular, mitochondrial fission allows for selective segregation of damaged mitochondria, which are afterward eliminated by autophagy. Unfortunately, recent evidence indicates that mitochondrial dynamics and autophagy are progressively impaired over time, contributing to the aging process. This suggests that restoration of these mechanisms could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of the close relationship between mitochondrial dynamics, mitophagy, oxidative stress, and aging, with a particular focus on the heart.
PMCID: PMC4124219  PMID: 25132912
8.  Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging 
PLoS Computational Biology  2012;8(6):e1002576.
Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the ‘mitochondrial infectious damage adaptation’ (MIDA) model according to which a deceleration of fusion–fission cycles reflects a systemic adaptation increasing life span.
Author Summary
Mitochondria are organelles that play a central role as ‘cellular power plants’. The cellular organization of these organelles involves a dynamic spatial network where mitochondria constantly undergo fusion and fission associated with the mixing of their molecular content. Together with the processes of mitophagy and biogenesis of mitochondrial mass, this results into a cellular surveillance system for maintaining their bioenergetic quality. The accumulation of molecular damage in mitochondria is associated with various human disorders and with aging. However, how these processes affect aging and how they can be reconciled with existing aging theories is just at the beginning to be considered. Mathematical modeling allows simulating the dynamics of mitochondrial quality control during aging in silico and leads to the ‘mitochondrial infectious damage adaptation’ (MIDA) model of aging. It reconciles a number of counterintuitive observations obtained during the last decade including infection-like processes of molecular damage spread, the reduction of fusion and fission rates during cellular aging, and observed life span extension for reduced mitochondrial fission. Interestingly, the MIDA model suggests that a reduction in mitochondrial dynamics rather than being merely a sign or even cause of aging, may actually reflect a systemic adaptation to prolong organismic life span.
PMCID: PMC3386171  PMID: 22761564
9.  Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health☆☆☆ 
Biochimica et Biophysica Acta  2014;1840(4):1254-1265.
The maintenance of cell metabolism and homeostasis is a fundamental characteristic of living organisms. In eukaryotes, mitochondria are the cornerstone of these life supporting processes, playing leading roles in a host of core cellular functions, including energy transduction, metabolic and calcium signalling, and supporting roles in a number of biosynthetic pathways. The possession of a discrete mitochondrial genome dictates that the maintenance of mitochondrial ‘fitness’ requires quality control mechanisms which involve close communication with the nucleus.
Scope of review
This review explores the synergistic mechanisms that control mitochondrial quality and function and ensure cellular bioenergetic homeostasis. These include antioxidant defence mechanisms that protect against oxidative damage caused by reactive oxygen species, while regulating signals transduced through such free radicals. Protein homeostasis controls import, folding, and degradation of proteins underpinned by mechanisms that regulate bioenergetic capacity through the mitochondrial unfolded protein response. Autophagic machinery is recruited for mitochondrial turnover through the process of mitophagy. Mitochondria also communicate with the nucleus to exact specific transcriptional responses through retrograde signalling pathways.
Major conclusions
The outcome of mitochondrial quality control is not only reliant on the efficient operation of the core homeostatic mechanisms but also in the effective interaction of mitochondria with other cellular components, namely the nucleus.
General significance
Understanding mitochondrial quality control and the interactions between the organelle and the nucleus will be crucial in developing therapies for the plethora of diseases in which the pathophysiology is determined by mitochondrial dysfunction. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
•Mitochondria are critical components of the eukaryotic cell, responsible for diverse ranges of functions.•While ROS are damaging in excess amounts, low levels are essential signals in homeostasis.•Mitophagy is a highly regulated form of autophagy regulated by PINK1 and Parkin.•Transcription factors activate and coordinate the expression of both nuclear and mitochondrial genes.
PMCID: PMC3970188  PMID: 24211250
Mitochondria; Quality control; Antioxidant defence; Mitophagy; Retrograde signalling; Protein homeostasis
10.  Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of Aging 
Antioxidants & Redox Signaling  2010;12(4):503-535.
It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. These cells are rarely or not at all replaced during life and can be as old as the whole organism. The inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged structures completely results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin, an intralysosomal indigestible material. In this review, we stress the importance of crosstalk between mitochondria and lysosomes in aging. The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced turnover of effective mitochondria. The latter not only are functionally deficient but also produce increased amounts of reactive oxygen species, prompting lipofuscinogenesis. Moreover, defective and enlarged mitochondria are poorly autophagocytosed and constitute a growing population of badly functioning organelles that do not fuse and exchange their contents with normal mitochondria. The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival. Antioxid. Redox Signal. 12, 503–535.
ROS, Mitochondrial Damage, and Aging
Biomolecular damage under normal conditions
Imperfect turnover of damaged biologic structures
Major targets of ROS attack: mitochondria and lysosomes
Mitochondrial Fusion, Fission, and Biogenesis
The role of mitochondrial dynamics
Mitochondrial fusion
Mitochondrial fission
Mitochondrial biogenesis
Mitochondrial Proteolytic Systems
Mitochondrial Turnover by Autophagy
The main functions of the lysosomal compartment
Autophagic degradation of mitochondria (mitophagy)
Lipofuscin Formation and Its Influence on Autophagy
Influence of labile iron and ROS on lipofuscin formation
Consequences of the nondegradability of lipofuscin
Disease-related accumulation of intralysosomal and extralysosomal waste
Imperfect Mitochondrial Turnover and Postmitotic Cellular Aging
Age-related accumulation of defective mitochondria within postmitotic cells
Age-related decline in autophagy and Lon protease activity accelerates mitochondrial damage
Enlarged mitochondria are resistant to degradation and do not fuse with normal ones
Mechanisms of the age-related accumulation of mitochondria with homoplasmic mtDNA mutations
Decreased mitochondrial biogenesis in aged cells
Summary and Conclusions
PMCID: PMC2861545  PMID: 19650712
11.  Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging 
Neurobiology of disease  2010;43(1):46-51.
Macroautophagy is a cellular process by which cytosolic components and organelles are degraded in double-membrane bound structures upon fusion with lysosomes. A pathway for selective degradation of mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to neurons, because of the constant need for high levels of energy production in this cell type. Although much remains to be learned about mitophagy, it appears that the regulation of mitophagy shares key steps with the macroautophagy pathway, while exhibiting distinct regulatory steps specific for mitochondrial autophagic turnover. Mitophagy is emerging as an important pathway in neurodegenerative disease, and has been linked to the pathogenesis of Parkinson’s disease through the study of recessively inherited forms of this disorder, involving PINK1 and Parkin. Recent work indicates that PINK1 and Parkin together maintain mitochondrial quality control by regulating mitophagy. In the Purkinje cell degeneration (pcd) mouse, altered mitophagy may contribute to the dramatic neuron cell death observed in the cerebellum, suggesting that over-active mitophagy or insufficient mitophagy can both be deleterious. Finally, mitophagy has been linked to aging, as impaired macroautophagy over time promotes mitochondrial dysfunction associated with the aging process. Understanding the role of mitophagy in neural function, neurodegenerative disease, and aging represents an essential goal for future research in the autophagy field.
PMCID: PMC3096708  PMID: 20887789
12.  Mitochondrial dynamics and mitochondrial quality control 
Redox Biology  2014;4:6-13.
Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via autophagy (mitophagy) is thus critical for cellular homeostasis and function. Mitochondria are reticular organelles that have high plasticity for their dynamic structures and constantly undergo fission and fusion as well as movement through the cytoskeleton. In this review, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. We also discuss multiple pathways leading to the quality control of mitochondria in addition to the traditional mitophagy pathway under different conditions.
Graphical abstract
•Mitochondrial dynamics including mitochondrial fission/fusion and mitochondrial movement regulate mitochondrial homeostasis and quality.•Damaged mitochondria are removed via multiple mechanisms including mitophagy, mitochondrial derived vesicles and mitochondrial spheroids.•Mitophagy can occur in a Parkin-dependent or independent manner.•Parkin also regulates the formation of mitochondrial derived vesicles and mitochondrial spheroids.
PMCID: PMC4309858  PMID: 25479550
APAP, acetaminophen; Bag4, Bcl2-associated athanogene 4; Bcl2L1, Bcl-2 like 1; BNIP3, Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3; CCCP, m-chloro phenyl hydrazine; Clec16a, C-type lectin domain family 16, member A; Drp1, dynamin-related protein 1; Fis1, mitochondrial fission 1; FUNDC1, Fun14 domain containing 1; Hif-1, hypoxia-inducing factor 1; HSPA1L, heat shock 70 kDa protein 1-like; LC3, microtubule-associated protein 1 light-chain 3; LIR, LC3-interacting region; MEFs, mouse embryonic fibroblasts; Mff, mitochondria fission factor; Mfn1, mitofusin 1; Mfn2, mitofusin 2; MDV, mitochondria-derived vesicles; MID49, mitochondrial dynamics protein of 49 kDa; Miro, mitochondrial Rho GTPase; MUL1, mitochondrial ubiquitin ligase 1; Nrdp1, neuregulin receptor degradation protein 1; OPA1, optic atrophy 1; PARL, presenilin-associatedrhomboid-like; PGAM5, phosphoglycerate mutase family member 5; PINK1, PTEN-induced putative kinase 1; ROS, reactive oxygen species; Smurf1, Smad-specific E3 ubiquitin protein ligase 1; SQSTM1, sequestosome 1; SNPH, syntaphilin; TOMM7, translocase of outer mitochondrial membrane 7; TOMM20, translocase of outer mitochondrial membrane 20; UBA, ubiquitin-associated; Usp30, ubiquitin-specific peptidase 30; VDAC, voltage-dependent anion channel; Autophagy; Mitophagy; Parkin; Mitochondrial spheroids
13.  Mitochondrial Dynamics in Cardiovascular Health and Disease 
Antioxidants & Redox Signaling  2013;19(4):400-414.
Significance: Mitochondria are dynamic organelles capable of changing their shape and distribution by undergoing either fission or fusion. Changes in mitochondrial dynamics, which is under the control of specific mitochondrial fission and fusion proteins, have been implicated in cell division, embryonic development, apoptosis, autophagy, and metabolism. Although the machinery for modulating mitochondrial dynamics is present in the cardiovascular system, its function there has only recently been investigated. In this article, we review the emerging role of mitochondrial dynamics in cardiovascular health and disease. Recent Advances: Changes in mitochondrial dynamics have been implicated in vascular smooth cell proliferation, cardiac development and differentiation, cardiomyocyte hypertrophy, myocardial ischemia-reperfusion injury, cardioprotection, and heart failure. Critical Issues: Many of the experimental studies investigating mitochondrial dynamics in the cardiovascular system have been confined to cardiac cell lines, vascular cells, or neonatal cardiomyocytes, in which mitochondria are distributed throughout the cytoplasm and are free to move. However, in the adult heart where mitochondrial movements are restricted by their tightly-packed distribution along myofibrils or beneath the subsarcolemma, the relevance of mitochondrial dynamics is less obvious. The investigation of transgenic mice deficient in cardiac mitochondrial fission or fusion proteins should help elucidate the role of mitochondrial dynamics in the adult heart. Future Directions: Investigating the role of mitochondrial dynamics in cardiovascular health and disease should result in the identification of novel therapeutic targets for treating patients with cardiovascular disease, the leading cause of death and disability globally. Antioxid. Redox Signal. 19, 400—414.
PMCID: PMC3699895  PMID: 22793879
14.  Mitochondrial dynamics–fusion, fission, movement, and mitophagy–in neurodegenerative diseases 
Human Molecular Genetics  2009;18(R2):R169-R176.
Neurons are metabolically active cells with high energy demands at locations distant from the cell body. As a result, these cells are particularly dependent on mitochondrial function, as reflected by the observation that diseases of mitochondrial dysfunction often have a neurodegenerative component. Recent discoveries have highlighted that neurons are reliant particularly on the dynamic properties of mitochondria. Mitochondria are dynamic organelles by several criteria. They engage in repeated cycles of fusion and fission, which serve to intermix the lipids and contents of a population of mitochondria. In addition, mitochondria are actively recruited to subcellular sites, such as the axonal and dendritic processes of neurons. Finally, the quality of a mitochondrial population is maintained through mitophagy, a form of autophagy in which defective mitochondria are selectively degraded. We review the general features of mitochondrial dynamics, incorporating recent findings on mitochondrial fusion, fission, transport and mitophagy. Defects in these key features are associated with neurodegenerative disease. Charcot-Marie-Tooth type 2A, a peripheral neuropathy, and dominant optic atrophy, an inherited optic neuropathy, result from a primary deficiency of mitochondrial fusion. Moreover, several major neurodegenerative diseases—including Parkinson's, Alzheimer's and Huntington's disease—involve disruption of mitochondrial dynamics. Remarkably, in several disease models, the manipulation of mitochondrial fusion or fission can partially rescue disease phenotypes. We review how mitochondrial dynamics is altered in these neurodegenerative diseases and discuss the reciprocal interactions between mitochondrial fusion, fission, transport and mitophagy.
PMCID: PMC2758711  PMID: 19808793
15.  Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production 
eLife  2014;3:e03558.
Mitochondrial fusion and fission affect the distribution and quality control of mitochondria. We show that Marf (Mitochondrial associated regulatory factor), is required for mitochondrial fusion and transport in long axons. Moreover, loss of Marf leads to a severe depletion of mitochondria in neuromuscular junctions (NMJs). Marf mutants also fail to maintain proper synaptic transmission at NMJs upon repetitive stimulation, similar to Drp1 fission mutants. However, unlike Drp1, loss of Marf leads to NMJ morphology defects and extended larval lifespan. Marf is required to form contacts between the endoplasmic reticulum and/or lipid droplets (LDs) and for proper storage of cholesterol and ecdysone synthesis in ring glands. Interestingly, human Mitofusin-2 rescues the loss of LD but both Mitofusin-1 and Mitofusin-2 are required for steroid-hormone synthesis. Our data show that Marf and Mitofusins share an evolutionarily conserved role in mitochondrial transport, cholesterol ester storage and steroid-hormone synthesis.
eLife digest
Mitochondria are the main source of energy for cells. These vital and highly dynamic organelles continually change shape by fusing with each other and splitting apart to create new mitochondria, repairing and replacing those damaged by cell stress.
For nerve impulses to be transmitted across the gaps (called synapses) between nerve cells, mitochondria need to supply the very ends of the nerve fibers with energy. To do this, the mitochondria must be transported from the main body of the nerve cell to the tips of the nerve fibers. This may not happen if mitochondria are the wrong shape, size or damaged.
While searching for genetic mutations that disrupt nerve function in the fruit fly Drosophila, Sandoval et al. spotted mutations in a gene called Marf. Further investigations revealed that flies with mutant versions of Marf have small, round mitochondria, and their nerves cannot transmit signals to muscles when they are highly stimulated. This is because the mutant mitochondria are not easily transported along nerve fibers, and so not enough energy is supplied to the synapses. The synapses of the Marf mutants are also abnormally shaped. Sandoval et al. found that this is not because Marf is lost in the neurons themselves, but because it is lost from a hormone-producing tissue called the ring gland.
Another problem found in flies with mutated Marf genes is that they stop developing while in their larval stage. Sandoval et al. established that this could also be related to the loss of Marf from the ring gland. The Marf protein has two different functions in the ring gland: forming and storing droplets of fatty molecules used in hormone production, and synthesising a hormone that controls when a fly larva matures into the adult fly. This suggests that the lower levels of this hormone produced by Marf mutant flies underlies their prolonged larval stages and synapse defects.
Vertebrates (animals with backbones, such as humans) have two genes that are related to the fly's Marf gene. When the human forms of these genes were introduced into mutant flies that lack a working copy of Marf, hormone production was only restored if both genes were introduced together. This indicates that these genes have separate roles in vertebrates, but that these roles are both performed by the single fly gene.
The role of Marf in tethering mitochondria in the ring gland may allow us to better understand how this process affects hormone production and how the different parts of the cell communicate.
PMCID: PMC4215535  PMID: 25313867
mitochondria transport; Charcot-Marie-Tooth type 2A; Mfn1 and Mfn2; Drp1; Opa1; lipid droplets; endoplasmic reticulum; Drosophila melanogaster
16.  Mitochondrial Regulation of Cell Cycle and Proliferation 
Antioxidants & Redox Signaling  2012;16(10):1150-1180.
Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O2, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O2 utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis. Antioxid. Redox Signal. 16, 1150–1180.
I. Introduction
II. Introduction to Mitochondrial Biology
A. The physiology of mitochondria and redox biology
B. NO and mitochondrial redox metabolism
C. H2O2 and antagonistic antioxidant enzymes
D. The intermembrane space and the redox status
III. Mitochondrial Metabolism and Cell Proliferation
A. The Warburg effect: The mitochondrial control of proliferation
B. Mitochondria and redox control in normal and tumor cells
C. Stem cells, mitochondrial ROS metabolism, and differentiation
D. ROS and mitochondrial malignancy: The example of p53
E. The glycolytic effects for mitochondrial oxidative rate
F. Mitochondrial signaling in hypoxia
G. Mechanistic target of rapamycin (serine/threonine kinase)/Akt pathways
H. Hexokinase
I. The regulation of glycolysis and proliferation by the ubiquitination system
IV. ROS: From Proliferation to Cell Death
V. Kinases, Mitochondria, and Cell Cycle
A. The MAPK cascade
B. Akt/protein kinase B
C. Protein kinase C
D. Protein kinase A
VI. Mitochondrial Biogenesis
A. Transcriptional control of mitochondrial biogenesis
B. Mitochondrial biogenesis, NO, and ROS
VII. Mitochondrial Dynamics
A. Mitochondrial fusion
B. Mitochondrial fusion machinery and apoptosis
C. Mitochondrial fission
D. Mitochondrial fission machinery and apoptosis
E. Mitochondrial dynamics, NO, and ROS
VIII. Mitochondrial Biogenesis, Mitochondrial Dynamics, and Cell Cycle
IX. Concluding Remarks
PMCID: PMC3315176  PMID: 21967640
17.  Mitochondrial Dynamics in the Heart as a Novel Therapeutic Target for Cardioprotection 
Chonnam Medical Journal  2013;49(3):101-107.
Traditionally, mitochondria have been regarded solely as energy generators for cells; however, accumulating data have demonstrated that these complex organelles play a variety of roles within the cardiomyocyte that extend beyond this classic function. Mitochondrial dynamics involves mitochondrial movements and morphologic alterations by tethering, fusion, and fission, which depend on cellular energy requirements and metabolic status. Many studies have indicated that mitochondrial dynamics may be a fundamental component of the maintenance of normal cellular homeostasis and cardiac function. Mitochondrial dynamics is controlled by the protein machinery responsible for mitochondrial fusion and fission, but cardiomyocytes are densely packed as part of an intricate cytoarchitecture for efficient and imbalanced contraction; thus, mitochondrial dynamics in the adult heart are restricted and occur more slowly than in other organs. Cardiac mitochondrial dynamics is important for cardiac physiology in diseased conditions such as ischemia-reperfusion (IR) injury. Changes in mitochondrial morphology through modulation of the expression of proteins regulating mitochondrial dynamics demonstrates the beneficial effects on cardiac performance after IR injury. Thus, accurately defining the roles of mitochondrial dynamics in the adult heart can guide the identification and development of novel therapeutic targets for cardioprotection. Further studies should be performed to establish the exact mechanisms of mitochondrial dynamics.
PMCID: PMC3881204  PMID: 24400211
Mitochondrial dynamics; Myocardial reperfusion injury; Myocytes, cardiac
18.  Mitochondrial division/mitophagy inhibitor (Mdivi) Ameliorates Pressure Overload Induced Heart Failure 
PLoS ONE  2012;7(3):e32388.
We have previously reported the role of anti-angiogenic factors in inducing the transition from compensatory cardiac hypertrophy to heart failure and the significance of MMP-9 and TIMP-3 in promoting this process during pressure overload hemodynamic stress. Several studies reported the evidence of cardiac autophagy, involving removal of cellular organelles like mitochondria (mitophagy), peroxisomes etc., in the pathogenesis of heart failure. However, little is known regarding the therapeutic role of mitochondrial division inhibitor (Mdivi) in the pressure overload induced heart failure. We hypothesize that treatment with mitochondrial division inhibitor (Mdivi) inhibits abnormal mitophagy in a pressure overload heart and thus ameliorates heart failure condition.
Materials and Methods
To verify this, ascending aortic banding was done in wild type mice to create pressure overload induced heart failure and then treated with Mdivi and compared with vehicle treated controls.
Expression of MMP-2, vascular endothelial growth factor, CD31, was increased, while expression of anti angiogenic factors like endostatin and angiostatin along with MMP-9, TIMP-3 was reduced in Mdivi treated AB 8 weeks mice compared to vehicle treated controls. Expression of mitophagy markers like LC3 and p62 was decreased in Mdivi treated mice compared to controls. Cardiac functional status assessed by echocardiography showed improvement and there is also a decrease in the deposition of fibrosis in Mdivi treated mice compared to controls.
Above results suggest that Mdivi inhibits the abnormal cardiac mitophagy response during sustained pressure overload stress and propose the novel therapeutic role of Mdivi in ameliorating heart failure.
PMCID: PMC3313999  PMID: 22479323
19.  Mitochondrial morphology and cardiovascular disease 
Cardiovascular Research  2010;88(1):16-29.
Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy, although the majority of studies have been largely confined to non-cardiac cells. Despite the unique arrangement of mitochondria in the adult heart, emerging data suggest that changes in mitochondrial morphology may be relevant to various aspects of cardiovascular biology—these include cardiac development, the response to ischaemia–reperfusion injury, heart failure, diabetes mellitus, and apoptosis. Interestingly, the machinery required for altering mitochondrial shape in terms of the mitochondrial fusion and fission proteins are all present in the adult heart, but their physiological function remains unclear. In this article, we review the current developments in this exciting new field of mitochondrial biology, the implications for cardiovascular physiology, and the potential for discovering novel therapeutic strategies for treating cardiovascular disease.
PMCID: PMC2936127  PMID: 20631158
Mitochondrial morphology; Mitochondrial dynamics; Ischaemia–reperfusion injury; Mitochondrial fusion; Mitochondrial fission
20.  The Mitochondrial Dnm1-Like Fission Component Is Required for lga2-Induced Mitophagy but Dispensable for Starvation-Induced Mitophagy in Ustilago maydis 
Eukaryotic Cell  2012;11(9):1154-1166.
Selective elimination of mitochondria by autophagy (mitophagy) is a crucial developmental process to dispose of disintegrated or superflous organelles. However, little is known about underlying regulatory mechanisms. We have investigated mitophagy in response to conditional overexpression of the a2 mating-type locus gene lga2, which encodes a small mitochondrial protein critically involved in uniparental mitochondrial DNA inheritance during sexual development of Ustilago maydis. In this study, we show that conditional overexpression of lga2 efficiently triggers mitophagy that is dependent on atg8 and atg11, consistent with selective autophagy. lga2-triggered mitophagy is preceded by mitochondrial dysfunction, including depletion of mitochondrial RNA transcripts, and is mechanistically distinct from starvation-induced mitophagy despite a common requirement for atg11. In particular, lga2-triggered mitophagy strongly depends on the mitochondrial fission factor Dnm1, but it is only slightly affected by N-acetylcysteine, which is an inhibitor of starvation-induced mitophagy. To further delineate the role of mitochondrial fission, we analyzed lga2 effects in Δfis1 mutants. This revealed that mitochondrial fragmentation was only attenuated and mitophagy was largely unaffected. In further support of a Fis1-independent role for Dnm1, mitochondrial association of green fluorescent protein-tagged Dnm1 as well as Dnm1-opposed mitochondrial fusion during sexual development were fis1 independent. In conclusion, our results specify the role of the mitochondrial fission factor Dnm1 in mitophagy and uncover differences between mitophagy pathways in the same cellular system.
PMCID: PMC3445976  PMID: 22843561
21.  A Role for PGC-1 Coactivators in the Control of Mitochondrial Dynamics during Postnatal Cardiac Growth 
Circulation research  2013;114(4):626-636.
Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high capacity ATP production in heart. The transcriptional coactivators, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) α and β have been shown to regulate mitochondrial biogenesis in heart at the time of birth. The function of the PGC-1 coactivators in heart after birth is incompletely understood.
To assess the role of the PGC-1 coactivators during postnatal cardiac development and in the adult heart in mice.
Methods and Results
Conditional gene targeting was used in mice to explore the role of the PGC-1 coactivators during postnatal cardiac development and in adult heart. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion [mitofusin 1 (Mfn1), optic atrophy 1 (Opa1)] and fission [dynamin-related protein 1 (Drp1), fission protein 1 (Fis1)] was altered in hearts of PGC-1α/β-deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α (ERRα) upon a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that the PGC-1 coactivators are required for high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in adult heart.
These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.
PMCID: PMC4061768  PMID: 24366168
PGC-1 coactivators; mitochondrial fusion; cardiac energy metabolism; cardiomyopathy; mitofusin
22.  Mitophagy in neurodegeneration and aging 
Frontiers in Genetics  2012;3:297.
Macroautophagy is a cellular catabolic process that involves the sequestration of cytoplasmic constituents into double-membrane vesicles known as autophagosomes, which subsequently fuse with lysosomes, where they deliver their cargo for degradation. The main physiological role of autophagy is to recycle intracellular components, under conditions of nutrient deprivation, so as to supply cells with vital materials and energy. Selective autophagy also takes place in nutrient-rich conditions to rid the cell of damaged organelles or protein aggregates that would otherwise compromise cell viability. Mitophagy is a selective type of autophagy, whereby damaged or superfluous mitochondria are eliminated to maintain proper mitochondrial numbers and quality control. While mitophagy shares key regulatory factors with the general macroautophagy pathway, it also involves distinct steps, specific for mitochondrial elimination. Recent findings indicate that parkin and the phosphatase and tensin homolog-induced putative kinase protein 1 (PINK1), which have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, also regulate mitophagy and function to maintain mitochondrial homeostasis. Here, we survey the molecular mechanisms that govern the process of mitophagy and discuss its involvement in the onset and progression of neurodegenerative diseases during aging.
PMCID: PMC3525948  PMID: 23267366
aging; autophagy; neuron; mitochondria; mitophagy; neurodegeneration; parkin; PINK1
23.  Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease 
Antioxidants & Redox Signaling  2012;16(12):1492-1526.
Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several “anti-aging” strategies that treat CVDs and improve healthy cardiac aging.
I. Introduction
II. Aging and Epidemiology of CVDs
III. Physiology of Cardiac Aging
A. Ventricular changes
B. Valvular changes
IV. Animal Models of Cardiac Aging
A. Rodents
B. Drosophila
C. Canines
D. Nonhuman primates
V. Mitochondria and the Free Radical Theory of Aging
A. ROS and aging
B. Pleiotropy of ROS
C. Mitochondrial hormesis in aging
D. Mitochondrial turnover in aging
VI. Molecular Mechanisms of Cardiac Aging
A. Mitochondrial oxidative stress in cardiac aging
B. Neurohormonal regulation of cardiac aging
1. Renin-angiotensin system in cardiac aging
2. B-adrenergic signaling
3. Insulin/insulin-like growth factor 1/PI3K signaling
4. Natriuretic peptides signaling
C. Nutrient signaling in cardiac aging
D. Cardiac stem cell aging and telomeres
VII. Aging, Oxidative Stress, and CVDs
A. Oxidative stress and mitochondria in CVDs
1. The central role of mitochondrial oxidative stress and redox status in hypertension and heart failure
2. The role of mitochondria and oxidative stress in IR injury
B. Mechanisms of progression to heart failure in the aged hypertrophic heart
1. Increased cardiomyocyte death
2. ECM remodeling
3. Alteration of calcium handling proteins
4. Hypoxic response and angiogenesis
5. Mitochondrial dysfunction and abnormalities in energetics
VIII. Exercise, Cardiovascular Risks, and Cardiac Aging
IX. Emerging “Anti-Aging” Interventional Strategies for Cardiac Aging and CVDs
A. Dietary restriction
B. Antioxidant interventions
1. Nontargeted antioxidants
2. Mitochondrial-targeted antioxidants
a. TPP+conjugated antioxidants
b. Szeto-schiller peptides
C. Resveratrol and SIRTs activators
X. Conclusion and Future Directions
PMCID: PMC3329953  PMID: 22229339
24.  Mitochondrial Autophagy 
Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care.
PMCID: PMC4028823  PMID: 23985961
Autophagy; Heart; Mitochondria; Mitophagy; miRNA
25.  A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease 
Human Molecular Genetics  2010;19(R1):R28-R37.
The PTEN-induced putative kinase 1 (PINK1) is a mitochondrially targeted serine–threonine kinase, which is linked to autosomal recessive familial parkinsonism. Current literature implicates PINK1 as a pivotal regulator of mitochondrial quality control, promoting maintenance of respiring mitochondrial networks through cristae stabilization, phosphorylation of chaperones and possibly regulation of mitochondrial transport or autophagy. Pulse—chase studies indicate that PINK1 is rapidly processed into at least two shorter forms, which are distributed in both mitochondrial and cytosolic compartments. Through indirect regulation of mitochondrial proteases and Drp1, PINK1 may act to facilitate localized repair and fusion in response to minor mitochondrial stress. With severe mitochondrial damage, PINK1 facilitates aggregation and clearance of depolarized mitochondria through interactions with Parkin and possibly Beclin1. This switch in function most probably involves altered processing, post-translational modification and/or localization of PINK1, as overexpression of full-length PINK1 is required for mitochondrial Parkin recruitment. Under conditions of PINK1 deficiency, dysregulation of reactive oxygen species, electron transport chain function and calcium homeostasis trigger altered mitochondrial dynamics, indicating compromise of mitochondrial quality control mechanisms. Nevertheless, Parkin- and Beclin1-regulated mitochondrial autophagy remains effective at recycling PINK1-deficient mitochondria; failure of this final tier of mitochondrial quality control contributes to cell death. Thus, PINK1 plays a pivotal, multifactorial role in mitochondrial homeostasis. As autophagic recycling represents the final tier of mitochondrial quality control, whether PINK1 levels are enhanced or reduced, strategies to promote selective mitophagy and mitochondrial biogenesis may prove effective for multiple forms of Parkinson's disease.
PMCID: PMC2875056  PMID: 20385539

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