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Gino A Cortopassi - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress in inherited Mitochondrial Diseases
Free Radical Biology and Medicine, 2015Co-Authors: Genki Hayashi, Gino A CortopassiAbstract:Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial Diseases are the result of inherited defects in Mitochondrially expressed genes. One potential pathomechanism for Mitochondrial disease is oxidative stress. Oxidative stress can occur as the result of increased ROS production or decreased ROS protection. The role of oxidative stress in the five most common inherited Mitochondrial Diseases, Friedreich ataxia, LHON, MELAS, MERRF, and Leigh syndrome (LS), is discussed. Published reports of oxidative stress involvement in the pathomechanisms of these five Mitochondrial Diseases are reviewed. The strongest evidence for an oxidative stress pathomechanism among the five Diseases was for Friedreich ataxia. In addition, a meta-analysis was carried out to provide an unbiased evaluation of the role of oxidative stress in the five Diseases, by searching for "oxidative stress" citation count frequency for each disease. Of the five most common Mitochondrial Diseases, the strongest support for oxidative stress is for Friedreich ataxia (6.42%), followed by LHON (2.45%), MELAS (2.18%), MERRF (1.71%), and LS (1.03%). The increased frequency of oxidative stress citations was significant relative to the mean of the total pool of five Diseases (p<0.01) and the mean of the four non-Friedreich Diseases (p<0.0001). Thus there is support for oxidative stress in all five most common Mitochondrial Diseases, but the strongest, significant support is for Friedreich ataxia.
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Oxidative stress in inherited Mitochondrial Diseases
Free radical biology & medicine, 2015Co-Authors: Genki Hayashi, Gino A CortopassiAbstract:Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial Diseases are the result of inherited defects in Mitochondrially expressed genes. One potential pathomechanism for Mitochondrial disease is oxidative stress. Oxidative stress can occur as the result of increased ROS production or decreased ROS protection. The role of oxidative stress in the five most common inherited Mitochondrial Diseases, Friedreich ataxia, LHON, MELAS, MERRF, and Leigh syndrome (LS), is discussed. Published reports of oxidative stress involvement in the pathomechanisms of these five Mitochondrial Diseases are reviewed. The strongest evidence for an oxidative stress pathomechanism among the five Diseases was for Friedreich ataxia. In addition, a meta-analysis was carried out to provide an unbiased evaluation of the role of oxidative stress in the five Diseases, by searching for “oxidative stress” citation count frequency for each disease. Of the five most common Mitochondrial Diseases, the strongest support for oxidative stress is for Friedreich ataxia (6.42%), followed by LHON (2.45%), MELAS (2.18%), MERRF (1.71%), and LS (1.03%). The increased frequency of oxidative stress citations was significant relative to the mean of the total pool of five Diseases (p
Anu Suomalainen - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Diseases the contribution of organelle stress responses to pathology
Nature Reviews Molecular Cell Biology, 2018Co-Authors: Anu Suomalainen, Brendan J BattersbyAbstract:Mitochondrial Diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human Diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in Mitochondrial protein synthesis and Mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to Mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human Mitochondrial Diseases.
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Mitochondrial Diseases: the contribution of organelle stress responses to pathology
Nature Reviews Molecular Cell Biology, 2018Co-Authors: Anu Suomalainen, Brendan J BattersbyAbstract:Defects of Mitochondrial DNA (mtDNA) maintenance and Mitochondrial translation (mtDNA gene expression defects) are the most common causes of Mitochondrial disease, which was revealed by next-generation genetic tools. These disorders can be caused by mutations in nuclear or mtDNA genes. The diversity of clinical manifestations of mtDNA gene expression Diseases, which affect numerous tissues and can have a variable age of onset, cannot be explained only by a deficiency of Mitochondrial ATP synthesis. Recent evidence indicates that various Mitochondrial defects elicit specific stress responses, which affect both catabolic and anabolic metabolism at the organelle, cell and tissue level, and even signalling to the whole organism. Different types of Mitochondrial stress require specialized local and whole-cell quality control mechanisms to rectify the stress and the potential insult that could result from that stress. Deregulation of these quality control mechanisms can also contribute to disease. Activating transcription factors (ATFs) are highly conserved regulators of Mitochondrial stress responses and have been implicated in the remodelling of cellular as well as whole-body metabolism during Mitochondrial dysfunction. Evidence from mouse models of Mitochondrial Diseases indicates that targeting metabolism may offer promising therapies for treating patients with Mitochondrial disorders. Mitochondrial disorders encompass a broad range of pathologies, which manifest in different tissues, with variable age of onset and symptoms. Recent findings suggest that Mitochondrial stress responses, which are activated by defects in Mitochondrial genome maintenance and expression, contribute to cell and systemic dysfunction, and could explain the phenotypic variability of Mitochondrial disorders. Mitochondrial Diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human Diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in Mitochondrial protein synthesis and Mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to Mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human Mitochondrial Diseases.
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Mitochondrial Diseases.
Nature reviews. Disease primers, 2016Co-Authors: Gráinne S Gorman, Michio Hirano, Robert Mcfarland, Patrick F Chinnery, Salvatore Dimauro, Yasutoshi Koga, Anu Suomalainen, David R Thorburn, Massimo Zeviani, Douglass M TurnbullAbstract:Mitochondrial Diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and Mitochondrial DNA (mtDNA) that encode structural Mitochondrial proteins or proteins involved in Mitochondrial function. Mitochondrial Diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of Mitochondrial Diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with Mitochondrial Diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including Mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with Mitochondrial Diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress.
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Mechanisms of Mitochondrial Diseases.
Annals of medicine, 2011Co-Authors: Emil Ylikallio, Anu SuomalainenAbstract:Mitochondria are essential organelles with multiple functions, the most well known being the production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The Mitochondrial Diseases are defined by impairment of OXPHOS. They are a diverse group of Diseases that can present in virtually any tissue in either adults or children. Here we review the main molecular mechanisms of Mitochondrial Diseases, as presently known. A number of disease-causing genetic defects, either in the nuclear genome or in the mitochondria's own genome, Mitochondrial DNA (mtDNA), have been identified. The most classical genetic defect causing Mitochondrial disease is a mutation in a gene encoding a structural OXPHOS subunit. However, Mitochondrial Diseases can also arise through impaired mtDNA maintenance, defects in Mitochondrial translation factors, and various more indirect mechanisms. The putative consequences of Mitochondrial dysfunction on a cellular level are discussed.
Genki Hayashi - One of the best experts on this subject based on the ideXlab platform.
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oxidative stress in inherited Mitochondrial Diseases
Free Radical Biology and Medicine, 2015Co-Authors: Genki Hayashi, Gino A CortopassiAbstract:Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial Diseases are the result of inherited defects in Mitochondrially expressed genes. One potential pathomechanism for Mitochondrial disease is oxidative stress. Oxidative stress can occur as the result of increased ROS production or decreased ROS protection. The role of oxidative stress in the five most common inherited Mitochondrial Diseases, Friedreich ataxia, LHON, MELAS, MERRF, and Leigh syndrome (LS), is discussed. Published reports of oxidative stress involvement in the pathomechanisms of these five Mitochondrial Diseases are reviewed. The strongest evidence for an oxidative stress pathomechanism among the five Diseases was for Friedreich ataxia. In addition, a meta-analysis was carried out to provide an unbiased evaluation of the role of oxidative stress in the five Diseases, by searching for "oxidative stress" citation count frequency for each disease. Of the five most common Mitochondrial Diseases, the strongest support for oxidative stress is for Friedreich ataxia (6.42%), followed by LHON (2.45%), MELAS (2.18%), MERRF (1.71%), and LS (1.03%). The increased frequency of oxidative stress citations was significant relative to the mean of the total pool of five Diseases (p<0.01) and the mean of the four non-Friedreich Diseases (p<0.0001). Thus there is support for oxidative stress in all five most common Mitochondrial Diseases, but the strongest, significant support is for Friedreich ataxia.
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Oxidative stress in inherited Mitochondrial Diseases
Free radical biology & medicine, 2015Co-Authors: Genki Hayashi, Gino A CortopassiAbstract:Mitochondria are a source of reactive oxygen species (ROS). Mitochondrial Diseases are the result of inherited defects in Mitochondrially expressed genes. One potential pathomechanism for Mitochondrial disease is oxidative stress. Oxidative stress can occur as the result of increased ROS production or decreased ROS protection. The role of oxidative stress in the five most common inherited Mitochondrial Diseases, Friedreich ataxia, LHON, MELAS, MERRF, and Leigh syndrome (LS), is discussed. Published reports of oxidative stress involvement in the pathomechanisms of these five Mitochondrial Diseases are reviewed. The strongest evidence for an oxidative stress pathomechanism among the five Diseases was for Friedreich ataxia. In addition, a meta-analysis was carried out to provide an unbiased evaluation of the role of oxidative stress in the five Diseases, by searching for “oxidative stress” citation count frequency for each disease. Of the five most common Mitochondrial Diseases, the strongest support for oxidative stress is for Friedreich ataxia (6.42%), followed by LHON (2.45%), MELAS (2.18%), MERRF (1.71%), and LS (1.03%). The increased frequency of oxidative stress citations was significant relative to the mean of the total pool of five Diseases (p
Brendan J Battersby - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Diseases the contribution of organelle stress responses to pathology
Nature Reviews Molecular Cell Biology, 2018Co-Authors: Anu Suomalainen, Brendan J BattersbyAbstract:Mitochondrial Diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human Diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in Mitochondrial protein synthesis and Mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to Mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human Mitochondrial Diseases.
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Mitochondrial Diseases: the contribution of organelle stress responses to pathology
Nature Reviews Molecular Cell Biology, 2018Co-Authors: Anu Suomalainen, Brendan J BattersbyAbstract:Defects of Mitochondrial DNA (mtDNA) maintenance and Mitochondrial translation (mtDNA gene expression defects) are the most common causes of Mitochondrial disease, which was revealed by next-generation genetic tools. These disorders can be caused by mutations in nuclear or mtDNA genes. The diversity of clinical manifestations of mtDNA gene expression Diseases, which affect numerous tissues and can have a variable age of onset, cannot be explained only by a deficiency of Mitochondrial ATP synthesis. Recent evidence indicates that various Mitochondrial defects elicit specific stress responses, which affect both catabolic and anabolic metabolism at the organelle, cell and tissue level, and even signalling to the whole organism. Different types of Mitochondrial stress require specialized local and whole-cell quality control mechanisms to rectify the stress and the potential insult that could result from that stress. Deregulation of these quality control mechanisms can also contribute to disease. Activating transcription factors (ATFs) are highly conserved regulators of Mitochondrial stress responses and have been implicated in the remodelling of cellular as well as whole-body metabolism during Mitochondrial dysfunction. Evidence from mouse models of Mitochondrial Diseases indicates that targeting metabolism may offer promising therapies for treating patients with Mitochondrial disorders. Mitochondrial disorders encompass a broad range of pathologies, which manifest in different tissues, with variable age of onset and symptoms. Recent findings suggest that Mitochondrial stress responses, which are activated by defects in Mitochondrial genome maintenance and expression, contribute to cell and systemic dysfunction, and could explain the phenotypic variability of Mitochondrial disorders. Mitochondrial Diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human Diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in Mitochondrial protein synthesis and Mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to Mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human Mitochondrial Diseases.
Salvatore Dimauro - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Diseases in north america an analysis of the namdc registry
Neurology Genetics, 2020Co-Authors: Emanuele Barca, Valentina Emmanuele, Salvatore Dimauro, Yuelin Long, Victoria Cooley, Robert Schoenaker, Bruce H Cohen, Amel Karaa, Georgirene D Vladutiu, Richard HaasAbstract:Objective To describe clinical, biochemical, and genetic features of participants with Mitochondrial Diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. Methods This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists. Results One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical Mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the Mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with POLG1 and PDHA1 being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants. Conclusions The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.
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Mitochondrial Diseases.
Nature reviews. Disease primers, 2016Co-Authors: Gráinne S Gorman, Michio Hirano, Robert Mcfarland, Patrick F Chinnery, Salvatore Dimauro, Yasutoshi Koga, Anu Suomalainen, David R Thorburn, Massimo Zeviani, Douglass M TurnbullAbstract:Mitochondrial Diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and Mitochondrial DNA (mtDNA) that encode structural Mitochondrial proteins or proteins involved in Mitochondrial function. Mitochondrial Diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of Mitochondrial Diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with Mitochondrial Diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including Mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with Mitochondrial Diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress.
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A history of Mitochondrial Diseases
Journal of Inherited Metabolic Disease, 2011Co-Authors: Salvatore DimauroAbstract:This articles reviews the development of Mitochondrial medicine from the premolecular era (1962–1988), when Mitochondrial Diseases were defined on the basis of clinical examination, muscle biopsy, and biochemical criteria, through the molecular era, when the full complexity of these disorders became evident. In a chronological order, I have followed the introduction of new pathogenic concepts that have shaped a rational genetic classification of these clinically heterogeneous disorders. Thus, Mitochondrial DNA (mtDNA)-related Diseases can be divided into two main groups: those that impair Mitochondrial protein synthesis in toto, and those that affect specific respiratory chain proteins. Mutations in nuclear DNA can affect components of respiratory chain complexes (direct hits) or assembly proteins (indirect hits), but they can also impair mtDNA integrity (multiple mtDNA mutations), replication (mtDNA depletion), or mtDNA translation. Besides these disorders that affect the respiratory chain directly, defects in other Mitochondrial functions may also affect oxidative phosphorylation, including problems in Mitochondrial protein import, alterations of the inner Mitochondrial membrane lipid composition, and defects of Mitochondrial dynamics. The enormous and still ongoing progress in our understanding of Mitochondrial medicine was made possible by the intense collaboration of an international cadre of “mitochondriacs.” Having published my first paper on a patient with Mitochondrial myopathy 37 years ago (DiMauro et al., 1973 ), I feel qualified to write a history of the Mitochondrial Diseases, a fascinating, still evolving, and continuously puzzling area of medicine. In each section, I follow a chronological order of the salient discoveries and I show only the portraits of distinguished deceased mitochondriacs and those whose names became eponyms of Mitochondrial Diseases.
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Mitochondrial Diseases therapeutic approaches
Bioscience Reports, 2007Co-Authors: Salvatore Dimauro, Michelangelo MancusoAbstract:Therapy of Mitochondrial encephalomyopathies (defined restrictively as defects of the Mitochondrial respiratory chain) is woefully inadequate, despite great progress in our understanding of the molecular bases of these disorders. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10. There is increasing interest in the administration of reactive oxygen species scavengers both in primary Mitochondrial Diseases and in neurodegenerative Diseases directly or indirectly related to Mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with Mitochondrial myopathies due to Mitochondrial DNA (mtDNA) mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type Mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes (allotopic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders. Progress in each of these approaches provides some glimmer of hope for the future, although much work remains to be done.
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approaches to the treatment of Mitochondrial Diseases
Muscle & Nerve, 2006Co-Authors: Salvatore Dimauro, Michio Hirano, Eric A SchonAbstract:Therapy for Mitochondrial Diseases is woefully inadequate. However, lack of a cure does not equate with lack of treatment. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10 (CoQ10). There is increasing interest in the administration of reactive oxygen radicals (ROS) scavengers, both in primary Mitochondrial Diseases and in neurodegenerative Diseases. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but novel experimental approaches are being pursued. One important strategy is to decrease the ratio of mutant to wild-type Mitochondrial genomes ("gene shifting") by different means: (1) converting mutated Mitochondrial DNA (mtDNA) genes into normal nuclear DNA genes ("allotopic expression"); (2) importing cognate genes from other species ("xenotopic expression"); (3) correcting mtDNA mutations by importing specific restriction endonucleases; (4) selecting for respiratory function; and (5) inducing muscle regeneration. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders.