Mitochondrial diseases of the brain.
TL;DR: The role of mitochondrial dysfunction such as bioenergetics defects, mitochondrial DNA mutations, gene mutations, altered mitochondrial dynamics, impaired transcription and the association of mutated proteins with mitochondria in neurodegenerative disorders are discussed.
About: This article is published in Free Radical Biology and Medicine.The article was published on 2013-10-01. It has received 365 citations till now. The article focuses on the topics: mitochondrial fusion & DNM1L.
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TL;DR: This review examines the generation of reactive oxygen species by mammalian mitochondria, and the status of different sites of production in redox signaling and pathology, and identifies specific suppressors of two sites that allow the cellular roles of mitochondrial superoxide/hydrogen peroxide production to be investigated without catastrophic confounding bioenergetic effects.
694 citations
TL;DR: The opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies are discussed, and a small number of agents have entered clinical trials.
Abstract: Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.
441 citations
TL;DR: The purpose of this review was to present the current status of the knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment.
Abstract: Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.
321 citations
Cites background from "Mitochondrial diseases of the brain..."
...In addition to this, studies proved that mitochondria have an association with mutated proteins in neurodegenerative diseases [10]....
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...There are several evidence to suggest that sirtuins as the transcriptional regulators may have potential therapeutic effects on a several chronic age-related and aggregate-forming neurodegenerative diseases including AD, PD, HD, and ALS....
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...Taken together, induction or improvement of mitochondrial biogenesis may be considered as a novel therapeutic target and confirm a modern neuroprotective approach for most of diseases such as neurodegenerative diseases including AD, PD, HD, and ALS in the near future [92] (Figure 3)....
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...Dysfunction of mitochondrial electron transport chain (ETC.) complexes has been associated with the pathogenesis of the most common chronic age-related neurodegenerative diseases which associated with misfolding protein aggregation including AD, PD, HD, and ALS [47,72,73]....
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...Prototypical examples of the most common chronic neurodegenerative diseases associated with aging and aggregation of misfolded proteins are AD, PD, HD, and ALS....
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TL;DR: The current knowledge linking mitochondria-dependent signaling pathways to muscle homeostasis in aging and disease is outlined and the resulting implications for the development of novel therapeutic approaches to prevent muscle loss are outlined.
Abstract: Loss of muscle mass and force occurs in many diseases such as disuse/inactivity, diabetes, cancer, renal, and cardiac failure and in aging-sarcopenia. In these catabolic conditions the mitochondrial content, morphology and function are greatly affected. The changes of mitochondrial network influence the production of reactive oxygen species (ROS) that play an important role in muscle function. Moreover, dysfunctional mitochondria trigger catabolic signaling pathways which feed-forward to the nucleus to promote the activation of muscle atrophy. Exercise, on the other hand, improves mitochondrial function by activating mitochondrial biogenesis and mitophagy, possibly playing an important part in the beneficial effects of physical activity in several diseases. Optimized mitochondrial function is strictly maintained by the coordinated activation of different mitochondrial quality control pathways. In this review we outline the current knowledge linking mitochondria-dependent signaling pathways to muscle homeostasis in aging and disease and the resulting implications for the development of novel therapeutic approaches to prevent muscle loss.
302 citations
TL;DR: Some of the new findings regarding the control of mitochondrial gene expression by PGC‐1 coactivators in a tissue‐specific context are discussed, as well as newly‐uncovered functions of P GC‐1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer.
Abstract: Members of the PGC-1 family of coactivators have been revealed as key players in the regulation of energy metabolism. Early gain- and loss-of-function studies led to the conclusion that all members of the PGC-1 family (PGC-1α, PGC-1β and PRC) play redundant roles in the control of mitochondrial biogenesis by regulating overlapping gene expression programs. Regardless of this, all PGC-1 coactivators also appeared to differ in the stimuli to which they respond to promote mitochondrial gene expression. Although PGC-1α was found to be induced by different physiological or pharmacological cues, PGC-1β appeared to be unresponsive to such stimuli. Consequently, it has long been widely accepted that PGC-1α acts as a mediator of mitochondrial biogenesis induced by cues that signal high-energy needs, whereas the role of PGC-1β is restricted to the maintenance of basal mitochondrial function. By contrast, the function of PRC appears to be restricted to the regulation of gene expression in proliferating cells. However, recent studies using tissue-specific mouse models that lack or overexpress different PGC-1 coactivators have provided emerging evidence not only supporting new roles for PGC-1s, but also redefining some of the paradigms related to the precise function and mode of action of PGC-1 coactivators in mitochondrial biogenesis. The present review discusses some of the new findings regarding the control of mitochondrial gene expression by PGC-1 coactivators in a tissue-specific context, as well as newly-uncovered functions of PGC-1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer.
287 citations
References
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TL;DR: Treatments targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria hold great promise in ageing-related neurodegenerative diseases.
Abstract: Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.
5,368 citations
"Mitochondrial diseases of the brain..." refers background in this paper
...of mitochondrial dysfunction in familial PD pathogenesis [2, 3, 77-80]....
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...different pathogenic mechanisms have been identified in the CNS and peripheral tissues during the disease course in ALS, but mitochondrial and bioenergetic defects are implicated widely in ALS pathogenesis[2]....
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...Deficiency of FXN leads to an accumulation of iron in the mitochondria, enhanced cellular iron uptake and impaired activity of Fe-S cluster enzymes[2]....
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TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
4,872 citations
"Mitochondrial diseases of the brain..." refers background in this paper
...of mitochondrial dysfunction in familial PD pathogenesis [2, 3, 77-80]....
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...form of autosomal dominant familial PD [77, 78, 81-83]....
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TL;DR: It is proposed that this chemical selectively damages cells in the substantia nigra in patients who developed marked parkinsonism after using an illicit drug intravenously.
Abstract: Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
4,705 citations
"Mitochondrial diseases of the brain..." refers background in this paper
...mitochondrial complex-I of the electron transport chain, which suggested a specific role of mitochondrial dysfunction in the pathogenesis of PD [4, 5]....
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TL;DR: RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in P GC-1alpha acetylation and an increase in PGC-1 alpha activity.
3,740 citations
"Mitochondrial diseases of the brain..." refers background in this paper
...Resveratrol decreases PGC1α acetylation, which causes increased PGC1α activity, increased mitochondrial biogenesis and improved motor function in mice [466]....
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