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Abstract

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

Preconditioning

Postconditioning

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

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.

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.

Summary

Mitochondrial dysfunction is an important intracellular lesion associated with a wide variety of diseases including neurodegenerative disorders. In addition to aging, oxidative stress and mitochondrial DNA mutations, recent studies have implicated a role for the mitochondrial accumulation of proteins such as plasma membrane associated amyloid precursor protein (APP) and cytosolic alpha synuclein in the pathogenesis of mitochondrial dysfunction in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. Both of these proteins contain cryptic mitochondrial targeting signals, which drive their transport across mitochondria. In general, mitochondrial entry of nuclear coded proteins is assisted by import receptors situated in both outer and inner mitochondrial membranes. A growing number of evidence suggests that APP and alpha synclein interact with import receptors to gain entry into mitochondrial compartment. Additionally, carboxy terminal cleaved product of APP, ∼ 4kDa Abeta, is also transported into mitochondria with the help of mitochondrial outer membrane import receptors. This review focuses on the mitochondrial targeting and accumulation of these two structurally different proteins and the mode of mechanism by which they affect the physiological functions of mitochondria

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.

By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders - Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.

Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases. A deeper understanding of the remarkably dynamic nature of mitochondria, characterized by a delicate balance of fission and fusion, has helped to fertilize a recent wave of new studies demonstrating abnormal mitochondrial dynamics in neurodegenerative diseases. This review highlights mitochondrial dysfunction and abnormal mitochondrial dynamics in Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease and discusses how these abnormal mitochondrial dynamics may contribute to mitochondrial and neuronal dysfunction. We propose that abnormal mitochondrial dynamics represents a key common pathway that mediates or amplifies mitochondrial dysfunction and neuronal dysfunction during the course of 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.

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.

Abstract

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.

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.

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.

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

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.

SUMMARY

Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.

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.

Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach.

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

We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson's disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson's disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson's disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson's disease.

Abstract

Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron–sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment. Antioxid. Redox Signal. 13, 0000–0000.

Introduction and History

Clinical Features and Pathogenesis of Friedreich Ataxia

Epidemiology and clinical features

Pathophysiology

Mutations in the FXN Gene Cause FRDA

Mapping and cloning of the FXN gene

Structure and regulation of the FXN gene

Developmental expression of the FXN gene

Molecular mechanism of GAA triplet-repeat expansion

Genotype–phenotype correlations

Point mutations

Frataxin Is a Unique Protein

Phylogeny and structure of frataxin

Frataxin maturation

Cellular function of frataxin

Frataxin Function in Cell Iron Use and Oxidative-Stress Defense

Frataxin is critical for Fe-S cluster assembly

Frataxin is involved in heme biosynthesis

Iron homeostasis

Iron-binding properties and oligomerization of frataxin

Regulation of cellular antioxidant defenses

Mitochondrial and nuclear genome integrity

Frataxin Is Involved in Development, Cell Death, and Cancer

Development in model organisms

Susceptibility to cell death and neuron degeneration

Cancer

Therapeutic Approaches for Treatment of Friedreich Ataxia

Evaluation of disease progression

Antioxidants and oxidative phosphorylation

Iron chelators

Molecules that increase frataxin levels

Conclusion

The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury.

A large body of evidence from post-mortem brain tissue and genetic analysis in man and biochemical and pathological studies in animal models (transgenic and toxin) of neurodegeneration suggest that mitochondrial dysfunction is a common pathological mechanism. Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology and interaction of pathogenic proteins with mitochondria leads to neuronal demise. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. This review discusses the potential therapeutic efficacy of creatine, coenzyme Q10, idebenone, synthetic triterpenoids, and mitochondrial targeted antioxidants (MitoQ) and peptides (SS-31) in in vitro studies and in animal models of Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's disease (AD). We have also reviewed the current status of clinical trials of creatine, coenzyme Q10, idebenone and MitoQ in neurodegenerative disorders. Further, we discuss newly identified therapeutic targets including PGC-1α and Sirtuins, which provide promise for future therapeutic developments in neurodegenerative disorders.

Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 (SOCS6) gene is a frequent event in human gastric cancer. In this study, we recapitulated the event of SOCS6 loss using a Lentivirus-based knockdown approach, and demonstrated the linkage between SOCS6 depletion and the suppression of programmed cell death. SOCS6 promotes intrinsic apoptosis, with increased Bax conformational change, mitochondrial targeting, and oligomerization. Most importantly, SOCS6 is targeted to mitochondria and induces mitochondrial fragmentation mediated through an increase in DRP1 fission activity. Here, we show that SOCS6 forms complex with DRP1 and the mitochondrial phosphatase PGAM5, attenuates DRP1 phosphorylation, and promotes DRP1 mitochondrial translocation. Based on mutation analyses, SOCS6-mediated apoptosis is tightly coupled to its ability to induce mitochondrial fission. This study demonstrates an important role for SOCS6 in modulating mitochondrial dynamics and apoptosis.

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.

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.