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1.  Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model 
BMC Neurology  2015;15:19.
Mitochondrial dysfunction is a hallmark of neurodegenerative diseases including Alzheimer’s disease (AD), with morphological and functional abnormalities limiting the electron transport chain and ATP production. A contributing factor of mitochondrial abnormalities is loss of nicotinamide adenine dinucleotide (NAD), an important cofactor in multiple metabolic reactions. Depletion of mitochondrial and consequently cellular NAD(H) levels by activated NAD glycohydrolases then culminates in bioenergetic failure and cell death. De Novo NAD+ synthesis from tryptophan requires a multi-step enzymatic reaction. Thus, an alternative strategy to maintain cellular NAD+ levels is to administer NAD+ precursors facilitating generation via a salvage pathway. We administered nicotinamide mononucleotide (NMN), an NAD+ precursor to APP(swe)/PS1(ΔE9) double transgenic (AD-Tg) mice to assess amelioration of mitochondrial respiratory deficits. In addition to mitochondrial respiratory function, we examined levels of full-length mutant APP, NAD+-dependent substrates (SIRT1 and CD38) in homogenates and fission/fusion proteins (DRP1, OPA1 and MFN2) in mitochondria isolated from brain. To examine changes in mitochondrial morphology, bigenic mice possessing a fluorescent protein targeted to neuronal mitochondria (CaMK2a-mito/eYFP), were administered NMN.
Mitochondrial oxygen consumption rates were examined in N2A neuroblastoma cells and non-synaptic brain mitochondria isolated from mice (3 months). Western blotting was utilized to assess APP, SIRT1, CD38, DRP1, OPA1 and MFN2 in brain of transgenic and non-transgenic mice (3–12 months). Mitochondrial morphology was assessed with confocal microscopy. One-way or two-way analysis of variance (ANOVA) and post-hoc Holm-Sidak method were used for statistical analyses of data. Student t-test was used for direct comparison of two groups.
We now demonstrate that mitochondrial respiratory function was restored in NMN-treated AD-Tg mice. Levels of SIRT1 and CD38 change with age and NMN treatment. Furthermore, we found a shift in dynamics from fission to fusion proteins in the NMN-treated mice.
This is the first study to directly examine amelioration of NAD+ catabolism and changes in mitochondrial morphological dynamics in brain utilizing the immediate precursor NMN as a potential therapeutic compound. This might lead to well-defined physiologic abnormalities that can serve an important role in the validation of promising agents such as NMN that target NAD+ catabolism preserving mitochondrial function.
PMCID: PMC4358858  PMID: 25884176
Alzheimer’s disease; Mitochondria; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Neurodegeneration
2.  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
3.  Dynamin-Related Protein 1 and Mitochondrial Fragmentation in Neurodegenerative Diseases 
Brain research reviews  2010;67(1-2):103-118.
The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of X in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others’, we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage.
PMCID: PMC3061980  PMID: 21145355
4.  Parkinson's Disease–Associated Kinase PINK1 Regulates Miro Protein Level and Axonal Transport of Mitochondria 
PLoS Genetics  2012;8(3):e1002537.
Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.
Author Summary
Parkinson's disease (PD) is the second most common neurodegenerative disease. It mainly affects movement in elderly people and was traditionally considered a sporadic disease with no known cause. Discoveries of genes associated with familial PD (FPD) have demonstrated that PD pathogenesis can be significantly influenced by an individual's genetic makeup. Understanding the functions of these FPD genes will allow better understanding of the sporadic PD cases. PINK1 and Parkin are genes associated with FPD that affect patients at an early age. Mutations in PINK1 and Parkin lead to the accumulation of damaged mitochondria, the powerhouse of the cell, as a result of impairments of the mitochondrial quality control system. However, the mechanism of PINK1/Parkin action remains poorly understood. Here we show that PINK1 and Parkin act together to regulate Miro, a key component of the mitochondrial transport machinery, and that altered activities of PINK1 cause aberrant mitochondrial transport. Regulation of mitochondrial transport may be a critical aspect of the mechanisms by which the PINK1/Parkin pathway governs mitochondrial quality control. Dysfunction of this process could contribute to the loss of DA neurons, the cardinal feature of PD, as well as the peripheral neuropathy symptom associated with particular PINK1 or Parkin mutations.
PMCID: PMC3291531  PMID: 22396657
5.  Mitochondrial Dynamics and Parkinson's Disease: Focus on Parkin 
Antioxidants & Redox Signaling  2012;16(9):935-949.
Significance: Parkinson’s disease (PD) is a prevalent neurodegenerative disease affecting millions of individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. To provide more effective medical therapy for PD, better understanding of the underlying causes of the disease is clearly necessary. Recent Advances: A broad range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Supporting this, mutations in several PD-linked genes are directly or indirectly linked to mitochondrial dysfunction. In particular, recent discoveries have identified parkin, whose mutations are causative of recessive parkinsonism, as a key regulator of mitochondrial homeostasis. Critical Issues: Parkin appears to be involved in the entire spectrum of mitochondrial dynamics, including organelle biogenesis, fusion/fission, and clearance via mitophagy. How a single protein can regulate such diverse mitochondrial events is as intriguing as it is amazing; the mechanism underlying this is currently under intense research. Here, we provide an overview of mitochondrial dynamics and its relationship with neurodegenerative diseases and discuss current evidence and controversies surrounding the role of parkin in mitochondrial quality control and its relevance to PD pathogenesis. Future Directions: Although the emerging field of parkin-mediated mitochondrial quality control has proven to be exciting, it is important to recognize that PD pathogenesis is likely to involve an intricate network of interacting pathways. Elucidating the reciprocity of pathways, particularly how other PD-related pathways potentially influence mitochondrial homeostasis, may hold the key to therapeutic development. Antioxid. Redox Signal. 16, 935–949.
PMCID: PMC3292756  PMID: 21668405
6.  Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases 
Apoptosis  2010;15(11):1354-1363.
Normal mitochondrial dynamics consist of fission and fusion events giving rise to new mitochondria, a process termed mitochondrial biogenesis. However, several neurodegenerative disorders manifest aberrant mitochondrial dynamics, resulting in morphological abnormalities often associated with deficits in mitochondrial mobility and cell bioenergetics. Rarely, dysfunctional mitochondrial occur in a familial pattern due to genetic mutations, but much more commonly patients manifest sporadic forms of mitochondrial disability presumably related to a complex set of interactions of multiple genes (or their products) with environmental factors (G × E). Recent studies have shown that generation of excessive nitric oxide (NO), in part due to generation of oligomers of amyloid-β (Aβ) protein or overactivity of the NMDA-subtype of glutamate receptor, can augment mitochondrial fission, leading to frank fragmentation of the mitochondria. S-Nitrosylation, a covalent redox reaction of NO with specific protein thiol groups, represents one mechanism contributing to NO-induced mitochondrial fragmentation, bioenergetic failure, synaptic damage, and eventually neuronal apoptosis. Here, we summarize our evidence in Alzheimer’s disease (AD) patients and animal models showing that NO contributes to mitochondrial fragmentation via S-nitrosylation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission. These findings may provide a new target for drug development in AD. Additionally, we review emerging evidence that redox reactions triggered by excessive levels of NO can contribute to protein misfolding, the hallmark of a number of neurodegenerative disorders, including AD and Parkinson’s disease. For example, S-nitrosylation of parkin disrupts its E3 ubiquitin ligase activity, and thereby affects Lewy body formation and neuronal cell death.
PMCID: PMC2978885  PMID: 20177970
S-Nitrosylation; Mitochondrial fragmentation; Dynamin-related protein 1; β-Amyloid; Alzheimer’s disease
7.  Integrating multiple aspects of mitochondrial dynamics in neurons: Age-related differences and dynamic changes in a chronic rotenone model 
Neurobiology of disease  2010;41(1):189-200.
Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson’s disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons.
PMCID: PMC3021420  PMID: 20850532
mitochondria; mitochondrial; fission; fusion; transport; Parkinson’s disease; dynamics; mitophagy; neurodegenerative; neuron; neurodegeneration
8.  How the Wnt signaling pathway protects from neurodegeneration: the mitochondrial scenario 
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration.
PMCID: PMC4419851  PMID: 25999816
Wnt; mitochondrial dynamics; permeability transition; Alzheimer’s disease; amyloid-beta; Drp1; electron microscopy
9.  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
10.  The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging 
Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer’s and Parkinson’s spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane – 40 kD (TOMM40) is associated with risk and age-of onset of late-onset AD, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction. In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer’s (AD) and Parkinson’s (PD) diseases. All but 36 of the >~1,500 mitochondrial proteins are encoded by the nucleus and are synthesized on cytoplasmic ribosomes, and most of these are imported into mitochondria through the TOM complex, of which TOM40 is the central pore, mediating communication between the cytoplasm and the mitochondrial interior. APP enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as Aβ and alpha-synuclein, readily pass through the pore and cause toxic effects by directly inhibiting mitochondrial enzymes. Healthy mitochondria normally import and degrade the PD-related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin-mediated mitophagy. Under normal circumstances, this process helps clear dysfunctional mitochondria and contributes to cellular health, but PINK1 mutations associated with PD exit mitochondria with intact membrane potentials, disrupting mitochondrial dynamics, leading to pathology. Thus, TOM40 plays a central role in the mitochondrial dysfunction that underlies age-related neurodegenerative diseases. Learning about the factors that control TOM40 levels and activity, and how TOM40, specifically, and the TOM complex, generally, interacts with potentially pathogenic proteins, will provide deeper insights to AD and PD pathogenesis, and possibly new targets for preventative and/or therapeutic treatments.
PMCID: PMC4346331  PMID: 25745640
TOMM40; Mitochondria; Alzheimer’s Disease; Parkinson’s Disease; Regulation Of Gene Expression; TOM Complex; APOE; SNCA; PARK2; PINK1
11.  Mitochondrial Dynamics and Neurodegeneration 
Mitochondria are key organelles in eukaryotic cells that not only generate adenosine triphosphate but also perform such critical functions as hosting essential biosynthetic pathways, calcium buffering, and apoptotic signaling. In vivo, mitochondria form dynamic networks that undergo frequent morphologic changes through fission and fusion. In neurons, the imbalance of mitochondrial fission/fusion can influence neuronal physiology, such as synaptic transmission and plasticity, and affect neuronal survival. Core components of the mitochondrial fission/fusion machinery have been identified through genetic studies in model organisms. Mutations in some of these genes in humans have been linked to rare neurodegenerative diseases such as Charcot-Marie-Tooth subtype 2A and autosomal dominant optic atrophy. Recent studies also have implicated aberrant mitochondrial fission/fusion in the pathogenesis of more common neurodegenerative diseases such as Parkinson’s disease. These studies establish mitochondrial dynamics as a new paradigm for neurodegenerative disease research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in disease intervention.
PMCID: PMC3045816  PMID: 19348710
12.  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
13.  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
14.  Mitochondrial dynamics in Parkinson's disease 
Experimental neurology  2009;218(2):247-256.
The unique energy demands of neurons require well-orchestrated distribution and maintenance of mitochondria. Thus, dynamic properties of mitochondria, including fission, fusion, trafficking, biogenesis, and degradation, are critical to all cells, but may be particularly important in neurons. Dysfunction in mitochondrial dynamics has been linked to neuropathies and is increasingly being linked to several neurodegenerative diseases, but the evidence is particularly strong, and continuously accumulating, in Parkinson's disease (PD). The unique characteristics of neurons that degenerate in PD may predispose those neuronal populations to susceptibility to alterations in mitochondrial dynamics. In addition, evidence from PD-related toxins supports that mitochondrial fission, fusion, and transport may be involved in pathogenesis. Furthermore, rapidly increasing evidence suggests that two proteins linked to familial forms of the disease, parkin and PINK1, interact in a common pathway to regulate mitochondrial fission/fusion. Parkin may also play a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Taken together, the current data suggests that mitochondrial dynamics may play a role in PD pathogenesis, and a better understanding of mitochondrial dynamics within the neuron may lead to future therapeutic treatments for PD, potentially aimed at some of the earliest pathogenic events.
PMCID: PMC2752687  PMID: 19332061
Parkinson disease; Parkinson's disease; mitochondria; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; parkin; PINK1; mitophagy
15.  Mitochondria as a Therapeutic Target for Aging and Neurodegenerative Diseases 
Current Alzheimer Research  2011;8(4):393-409.
Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases.
PMCID: PMC3295247  PMID: 21470101
Abnormal mitochondrial dynamics; Aging; Alzheimer’s disease; Huntington’s disease; Mitochondria; Mitochondria-targeted antioxidants; Neurodegenerative Disease; Parkinson’s disease
16.  S-Nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration 
Mitochondrion  2010;10(5):573-578.
Neurons are known to use large amounts of energy for their normal function and activity. In order to meet this demand, mitochondrial fission, fusion, and movement events (mitochondrial dynamics) control mitochondrial morphology, facilitating biogenesis and proper distribution of mitochondria within neurons. In contrast, dysfunction in mitochondrial dynamics results in reduced cell bioenergetics and thus contributes to neuronal injury and death in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease. We recently reported that amyloid-β peptide, thought to be a key mediator of AD pathogenesis, engenders S-nitrosylation and thus hyperactivation of the mitochondrial fission protein Drp1. This activation leads to excessive mitochondrial fragmentation, bioenergetic compromise, and synaptic damage in models of AD. Here, we provide an extended commentary on our findings of nitric oxide-mediated abnormal mitochondrial dynamics.
PMCID: PMC2918703  PMID: 20447471
S-Nitrosylation; Dynamin-related protein 1; Alzheimers’s disease; Mitochondrial fission
17.  Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster 
PLoS Genetics  2010;6(12):e1001237.
Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.
Author Summary
Parkinson's disease is the most common neurodegenerative disease affecting the aging population. Clinically it manifests as tremor, muscle rigidity, slow movement, and postural instability. Parkinson's disease is a chronic disorder, and its occurrence and progression are determined by genetic backgrounds and environmental factors. Although the most common forms of Parkinson's disease, the so-called “idiopathic” forms, generally affect people older than 50, some familial forms of the disease occur before age 40. Mutations in PINK1 and Parkin genes have been associated with the latter forms of Parkinson's disease. The inactivation of PINK1 or Parkin causes dysfunction of mitochondria, the powerhouse of the cell, leading to the degeneration of tissues such as the brain and muscle that have high energy demand. In an effort to understand how genetic mutations in PINK1 result in disease and to find effective ways to intervene, we have performed genetic studies in the model organism Drosophila melanogaster and found that reduced protein translation or increased autophagy can efficiently mitigate the phenotypes caused by PINK1 inactivation. Our result suggests that pharmacological manipulations of these newly identified PINK1-interacting pathways may prove beneficial for the treatment of Parkinson's disease.
PMCID: PMC3000346  PMID: 21151574
18.  Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics 
Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer’s Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics – continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics.
PMCID: PMC3856479  PMID: 24067127
DOA; LHON; Glaucoma; OPA1; OPA3; BNIP3; NMDA receptors; Oxidative stress; Mitochondrial fusion; Retinal ganglion cells; Glutamate excitotoxicity; Mitochondrial quality control; Mitochondrial optic neuropathies
19.  Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration 
In neurons, mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission. Additionally, mitochondria localize to the synapse, where they are critical for the mobilization of reserve pool vesicles and for neurotransmitter release. Previously, functional defects in mitochondria were considered to be downstream effects of neurodegenerative diseases. However, more recent findings suggest mitochondria may serve as key mediators in the onset and progression of some types of neurodegeneration. In this review, we explore the possible roles of altered mitochondrial function and dynamics in the pathogenesis of neurodegenerative disorders, with a particular focus on Alzheimer’s disease (AD) and Parkinson’s disease (PD), which have highlighted the important role of mitochondria in neurodegeneration. While inheritable diseases like Charcot-Marie-Tooth disease type 2A are concretely linked to gene mutations affecting mitochondrial function, the cause of mitochondrial dysfunction in primarily sporadic diseases such as AD and PD is less clear. Neuronal death in PD is associated with defects in mitochondrial function and dynamics arising from mutations in proteins affecting these processes, including α-synuclein, DJ-1, LRRK2, Parkin and Pink1. In the case of AD, however, the connection between mitochondria and the onset of neurodegeneration has been less clear. Recent findings, however, have implicated altered function of ER-mitochondria contact sites and amyloid beta- and/or tau-induced defects in mitochondrial function and dynamics in the pathogenesis of AD, suggesting that mitochondrial defects may act as key mediators in the pathogenesis of AD as well. With recent findings at hand, it may be postulated that defects in mitochondrial processes comprise key events in the onset of neurodegeneration.
PMCID: PMC3669018  PMID: 23711354
Mitochondria; Neurodegeneration; Parkinson’s; Alzheimer’s; Charcot-Marie-Tooth
20.  Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1 
PLoS Biology  2011;9(4):e1000612.
The mitochondrial signaling complex PKA/AKAP1 protects neurons against mitochondrial fragmentation and cell death by phosphorylating and inactivating the mitochondrial fission enzyme Drp1.
Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM) targeted form of the protein kinase A (PKA) catalytic subunit reshapes mitochondria into an interconnected network. Conversely, OMM-targeting of the PKA inhibitor PKI promotes mitochondrial fragmentation upstream of neuronal death. RNAi and overexpression approaches identify mitochondria-localized A kinase anchoring protein 1 (AKAP1) as a neuroprotective and mitochondria-stabilizing factor in vitro and in vivo. According to epistasis studies with phosphorylation site-mutant dynamin-related protein 1 (Drp1), inhibition of the mitochondrial fission enzyme through a conserved PKA site is the principal mechanism by which cAMP and PKA/AKAP1 promote both mitochondrial elongation and neuronal survival. Phenocopied by a mutation that slows GTP hydrolysis, Drp1 phosphorylation inhibits the disassembly step of its catalytic cycle, accumulating large, slowly recycling Drp1 oligomers at the OMM. Unopposed fusion then promotes formation of a mitochondrial reticulum, which protects neurons from diverse insults.
Author Summary
Mitochondria, the cellular powerhouse, are highly dynamic organelles shaped by opposing fission and fusion events. Research over the past decade has identified many components of the mitochondrial fission/fusion machinery and led to the discovery that mutations in genes coding for these proteins can cause human neurological diseases. While it is well established that mitochondrial shape changes are intimately involved in cellular responses to environmental stressors, we know very little about the mechanisms by which cells dynamically adjust mitochondrial form and function. In this report, we show that the scaffold protein AKAP1 brings the cAMP-dependent protein kinase PKA to the outer mitochondrial membrane to protect neurons from injury. The PKA/AKAP1 complex functions by inhibiting Drp1, an enzyme that mechanically constricts and eventually severs mitochondria. Whereas active, dephosphorylated Drp1 rapidly cycles between cytosol and mitochondria, phosphorylated Drp1 builds up in inactive mitochondrial complexes, allowing mitochondria to fuse into a neuroprotective reticulum. Our results suggest that altering the balance of kinase and phosphatase activities at the outer mitochondrial membrane may provide the basis for novel neuroprotective therapies.
PMCID: PMC3079583  PMID: 21526220
21.  Impairing the Mitochondrial Fission and Fusion Balance: A New Mechanism of Neurodegeneration 
Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, the cause of this dysfunction remains a mystery. Here, we discuss the potential role of mitochondrial fission and fusion in the onset and progression of neurodegenerative diseases. Specifically, we propose that an imbalance in mitochondrial fission and fusion may underlie both familial and sporadic neurodegenerative disorders. There is substantial evidence that links disruption of the mitochondrial fission and fusion equilibrium, resulting in abnormally long or short mitochondria, to neurodegeneration. First, hereditary mutations in the mitochondrial fusion GTPases optic atrophy-1 (OPA1) and mitofusin-2 (Mfn2) cause neuropathies in humans. In addition, recent findings report increased mitochondrial fission in Parkinson's disease (PD) models and induction of mitochondrial fission by two proteins, PTEN-induced kinase 1 (PINK1) and Parkin, which are mutant in familial forms of PD. Furthermore, mutant huntingtin, the disease-causing protein in Huntington's disease (HD), alters mitochondrial morphology and dynamics. Rotenone, a pesticide and inducer of PD symptoms, and amyloid-β (Aβ) peptide, which is causally linked to Alzheimer's disease (AD), initiate mitochondrial fission. Finally, mitochondrial fission is an early event in ischemic stroke and diabetic neuropathies. In sum, a growing body of research suggests that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments and cures for neurodegenerative diseases.
PMCID: PMC2605288  PMID: 19076450
Huntington's disease; Parkinson's disease; GTPases; OPA1; Mitofusins; Drp1; PINK1; Parkin
22.  Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer’s Disease? 
Molecular neurobiology  2010;41(2-3):87-96.
Mitochondria are dynamic organelles that undergo continuous fission and fusion, which could affect all aspects of mitochondrial function. Mitochondrial dysfunction has been well documented in Alzheimer’s disease (AD). In the past few years, emerging evidence indicates that an imbalance of mitochondrial dynamics is involved in the pathogenesis of AD. In this review, we discuss in detail the abnormal mitochondrial dynamics in AD and how such abnormal dynamics may impact mitochondrial and neuronal function and contribute to the course of disease. Based on this discussion, we propose that mitochondrial dynamics could be a potential therapeutic target for AD.
PMCID: PMC3129743  PMID: 20101529
Alzheimer’s disease; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Drug; Dimebon
23.  The Failure of Mitochondria Leads to Neurodegeneration: Do Mitochondria Need A Jump Start? 
Advanced drug delivery reviews  2009;61(14):1316-1323.
Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death. In this context, the regulation of mitochondrial function via therapeutic approaches may exert some salutary and neuroprotective mechanisms. Understanding the relationship of mitochondria-dependent pathogenesis may provide important pharmacological utility in the treatment of neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease. Indeed, the modulation of mitochondrial pathways is rapidly emerging as a novel therapeutic target. This review focuses on how mitochondria are involved in neurodegeneration and what therapeutics are available to target mitochondrial pathways.
PMCID: PMC2783929  PMID: 19716395
Neuroprotection; Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Parkinson’s disease; Therapeutics
Neuroscience  2011;196:251-264.
Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson’s disease (PD). PD brain tissues show evidence for mitochondrial respiratory chain Complex I deficiency. Pharmacological inhibitors of Complex I, such as rotenone, cause experimental parkinsonism. The cytoprotective protein DJ-1, whose deletion is sufficient to cause genetic PD, is also known to have mitochondria-stabilizing properties. We have previously shown that DJ-1 is over-expressed in PD astrocytes, and that DJ-1 deficiency impairs the capacity of astrocytes to protect co-cultured neurons against rotenone. Since DJ-1 modulated, astrocyte-mediated neuroprotection against rotenone may depend upon proper astrocytic mitochondrial functioning, we hypothesized that DJ-1 deficiency would impair astrocyte mitochondrial motility, fission/fusion dynamics, membrane potential maintenance, and respiration, both at baseline and as an enhancement of rotenone-induced mitochondrial dysfunction. In astrocyte-enriched cultures, we observed that DJ-1 knock-down reduced mitochondrial motility primarily in the cellular processes of both untreated and rotenone treated cells. In these same cultures, DJ-1 knock-down did not appreciably affect mitochondrial fission, fusion, or respiration, but did enhance rotenone-induced reductions in the mitochondrial membrane potential. In neuron–astrocyte co-cultures, astrocytic DJ-1 knock-down reduced astrocyte process mitochondrial motility in untreated cells, but this effect was not maintained in the presence of rotenone. In the same co-cultures, astrocytic DJ-1 knock-down significantly reduced mitochondrial fusion in the astrocyte cell bodies, but not the processes, under the same conditions of rotenone treatment in which DJ-1 deficiency is known to impair astrocyte-mediated neuroprotection. Our studies therefore demonstrated the following new findings: (i) DJ-1 deficiency can impair astrocyte mitochondrial physiology at multiple levels, (ii) astrocyte mitochondrial dynamics vary with sub-cellular region, and (iii) the physical presence of neurons can affect astrocyte mitochondrial behavior.
PMCID: PMC3490195  PMID: 21907265
rotenone; mitochondria; dynamics; motility; fission; fusion
25.  Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency 
Cell Death and Differentiation  2012;20(1):77-85.
Mitochondrial complex I dysfunction has long been associated with Parkinson's disease (PD). Recent evidence suggests that mitochondrial involvement in PD may extend beyond a sole respiratory deficit and also include perturbations in mitochondrial fusion/fission or ultrastructure. Whether and how alterations in mitochondrial dynamics may relate to the known complex I defects in PD is unclear. Optic atrophy 1 (OPA1), a dynamin-related GTPase of the inner mitochondrial membrane, participates in mitochondrial fusion and apoptotic mitochondrial cristae remodeling. Here we show that complex I inhibition by parkinsonian neurotoxins leads to an oxidative-dependent disruption of OPA1 oligomeric complexes that normally keep mitochondrial cristae junctions tight. As a consequence, affected mitochondria exhibit major structural abnormalities, including cristae disintegration, loss of matrix density and swelling. These changes are not accompanied by mitochondrial fission but a mobilization of cytochrome c from cristae to intermembrane space, thereby lowering the threshold for activation of mitochondria-dependent apoptosis by cell death agonists in compromised neurons. All these pathogenic changes, including mitochondrial structural remodeling and dopaminergic neurodegeneration, are abrogated by OPA1 overexpression, both in vitro and in vivo. Our results identify OPA1 as molecular link between complex I deficiency and alterations in mitochondrial dynamics machinery and point to OPA1 as a novel therapeutic target for complex I cytopathies, such as PD.
PMCID: PMC3524632  PMID: 22858546
Parkinson's disease; MPTP; rotenone; apoptosis

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