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Molecular and Cellular Neurosciences Sep 2023Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways... (Review)
Review
Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
Topics: Animals; Glutamine; MELAS Syndrome; Mitochondria; Neurodegenerative Diseases; Mitochondrial Diseases
PubMed: 37586651
DOI: 10.1016/j.mcn.2023.103887 -
Brain : a Journal of Neurology Jun 2016Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often... (Review)
Review
Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.
Topics: Animals; DNA, Mitochondrial; Disease Models, Animal; Drug Delivery Systems; Humans; Mitochondrial Diseases; Models, Biological; Molecular Targeted Therapy; Mutation; Stem Cell Transplantation
PubMed: 27190030
DOI: 10.1093/brain/aww081 -
Disease Models & Mechanisms Jun 2015Mitochondrial diseases are severe and largely untreatable. Owing to the many essential processes carried out by mitochondria and the complex cellular systems that... (Review)
Review
Mitochondrial diseases are severe and largely untreatable. Owing to the many essential processes carried out by mitochondria and the complex cellular systems that support these processes, these diseases are diverse, pleiotropic, and challenging to study. Much of our current understanding of mitochondrial function and dysfunction comes from studies in the baker's yeast Saccharomyces cerevisiae. Because of its good fermenting capacity, S. cerevisiae can survive mutations that inactivate oxidative phosphorylation, has the ability to tolerate the complete loss of mitochondrial DNA (a property referred to as 'petite-positivity'), and is amenable to mitochondrial and nuclear genome manipulation. These attributes make it an excellent model system for studying and resolving the molecular basis of numerous mitochondrial diseases. Here, we review the invaluable insights this model organism has yielded about diseases caused by mitochondrial dysfunction, which ranges from primary defects in oxidative phosphorylation to metabolic disorders, as well as dysfunctions in maintaining the genome or in the dynamics of mitochondria. Owing to the high level of functional conservation between yeast and human mitochondrial genes, several yeast species have been instrumental in revealing the molecular mechanisms of pathogenic human mitochondrial gene mutations. Importantly, such insights have pointed to potential therapeutic targets, as have genetic and chemical screens using yeast.
Topics: Animals; DNA, Fungal; Humans; Mitochondria; Mitochondrial Diseases; Models, Biological; Saccharomyces cerevisiae; Translational Research, Biomedical
PubMed: 26035862
DOI: 10.1242/dmm.020438 -
The Journal of Clinical Investigation Jan 2021Advancing proteomic and metabolomic technologies that integrate curated omic databases have crossed a threshold to enable their clinical utility. In this issue of the...
Advancing proteomic and metabolomic technologies that integrate curated omic databases have crossed a threshold to enable their clinical utility. In this issue of the JCI, Sharma et al. exploit emerging technologies to evaluate whether biomarkers identified in the mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome could refine disease characterization, uncover pathways to monitor therapeutic efficacy, and/or delineate disease-modifying targets. The authors analyzed blood and urine samples from patients with this genetic mitochondrial disease and elucidated proteins and metabolites related to NADH-reductive stress. These circulating biomarkers have intriguing clinical potential that implicate disease pathophysiology and may prove important biomarkers for the future management of MELAS.
Topics: Biomarkers; Humans; MELAS Syndrome; Mitochondrial Diseases; Proteomics; Stroke
PubMed: 33463543
DOI: 10.1172/JCI145158 -
Molecular Metabolism Jul 2020In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model...
OBJECTIVE
In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model of liver-specific Complex IV deficiency to study hepatic allostasis during respiratory viral infection.
METHODS
Mice with hepatic cytochrome c oxidase deficiency (LivCox10) were infected with aerosolized influenza, A/PR/8 (PR8), and euthanized on day five after infection following three days of symptoms. This time course is marked by a peak in inflammatory cytokines and mimics the timing of a common clinical scenario in which caregivers may first attempt to manage the illness at home before seeking medical attention. Metabolic decompensation and mitochondrial hepatopathy in mice were characterized by serum hepatic testing, histology, electron microscopy, biochemistry, metabolomics, and bioenergetic profiling.
RESULTS
Following influenza infection, LivCox10 mice displayed marked liver disease including hepatitis, enlarged mitochondria with cristae loss, and hepatic steatosis. This pathophysiology was associated with viremia. Primary hepatocytes from LivCox10 mice cocultured with WT Kupffer cells in the presence of PR8 showed enhanced lipid accumulation. Treatment of hepatocytes with recombinant TNFα implicated Kupffer cell-derived TNFα as a precipitant of steatosis in LivCox10 mice. Eliminating Kupffer cells or blocking TNFα in vivo during influenza infection mitigated the steatosis and mitochondrial morphologic changes.
CONCLUSIONS
Taken together, our data shift the narrative of metabolic decompensation in mitochondrial hepatopathy beyond the bioenergetic costs of infection to include an underlying susceptibility to immune-mediated damage. Moreover, our work suggests that immune modulation during metabolic decompensation in mitochondrial disease represents a future viable treatment strategy needing further exploration.
Topics: Allostasis; Animals; Cytochrome-c Oxidase Deficiency; Disease Models, Animal; Fatty Liver; Female; Hepatitis; Hepatocytes; Kupffer Cells; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondrial Diseases; Orthomyxoviridae Infections
PubMed: 32283081
DOI: 10.1016/j.molmet.2020.100981 -
Cellular and Molecular Life Sciences :... Jan 2018Mitochondrial protein synthesis is essential for the production of components of the oxidative phosphorylation system. RNA modifications in the mammalian mitochondrial... (Review)
Review
Mitochondrial protein synthesis is essential for the production of components of the oxidative phosphorylation system. RNA modifications in the mammalian mitochondrial translation apparatus play key roles in facilitating mitochondrial gene expression as they enable decoding of the non-conventional genetic code by a minimal set of tRNAs, and efficient and accurate protein synthesis by the mitoribosome. Intriguingly, recent transcriptome-wide analyses have also revealed modifications in mitochondrial mRNAs, suggesting that the concept of dynamic regulation of gene expression by the modified RNAs (the "epitranscriptome") extends to mitochondria. Furthermore, it has emerged that defects in RNA modification, arising from either mt-DNA mutations or mutations in nuclear-encoded mitochondrial modification enzymes, underlie multiple mitochondrial diseases. Concomitant advances in the identification of the mitochondrial RNA modification machinery and recent structural views of the mitochondrial translation apparatus now allow the molecular basis of such mitochondrial diseases to be understood on a mechanistic level.
Topics: Animals; Base Sequence; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Oxidative Phosphorylation; RNA; RNA, Messenger; RNA, Mitochondrial; RNA, Transfer
PubMed: 28752201
DOI: 10.1007/s00018-017-2598-6 -
Open Biology Sep 2021The genome of mitochondria, called mtDNA, is a small circular DNA molecule present at thousands of copies per human cell. MtDNA is packaged into nucleoprotein complexes... (Review)
Review
The genome of mitochondria, called mtDNA, is a small circular DNA molecule present at thousands of copies per human cell. MtDNA is packaged into nucleoprotein complexes called nucleoids, and the density of mtDNA packaging affects mitochondrial gene expression. Genetic processes such as transcription, DNA replication and DNA packaging alter DNA topology, and these topological problems are solved by a family of enzymes called topoisomerases. Within mitochondria, topoisomerases are involved firstly in the regulation of mtDNA supercoiling and secondly in disentangling interlinked mtDNA molecules following mtDNA replication. The loss of mitochondrial topoisomerase activity leads to defects in mitochondrial function, and variants in the dual-localized type IA topoisomerase TOP3A have also been reported to cause human mitochondrial disease. We review the current knowledge on processes that alter mtDNA topology, how mtDNA topology is modulated by the action of topoisomerases, and the consequences of altered mtDNA topology for mitochondrial function and human health.
Topics: Animals; DNA Topoisomerases; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 34547213
DOI: 10.1098/rsob.210168 -
Biochemical Society Transactions Oct 2018Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected... (Review)
Review
Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.
Topics: Animals; Antioxidants; Clinical Trials as Topic; Diet, Ketogenic; Genetic Therapy; Humans; Hypoxia; Mechanistic Target of Rapamycin Complex 1; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype; Reactive Oxygen Species; Sirolimus
PubMed: 30301846
DOI: 10.1042/BST20180134 -
Journal of Inherited Metabolic Disease Jan 2021Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular... (Review)
Review
Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease-modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.
Topics: Animals; Cell Transplantation; Clinical Trials as Topic; DNA, Mitochondrial; Dietary Supplements; Exercise Therapy; Free Radical Scavengers; Genetic Therapy; Humans; Hypoxia; Mitochondria; Mitochondrial Diseases; Mitochondrial Replacement Therapy; Mutation; Oxidative Phosphorylation; RNA, Transfer
PubMed: 32618366
DOI: 10.1002/jimd.12281 -
Mutagenesis Jun 2023Mitochondrial DNA mutation and toxicity have been linked to several inherited and acquired diseases; however, these are challenging to diagnose and characterize due to... (Review)
Review
Mitochondrial DNA mutation and toxicity have been linked to several inherited and acquired diseases; however, these are challenging to diagnose and characterize due to clinical and genetic heterogeneity. This review investigates current techniques for the analysis of mitochondrial perturbations, and novel, emerging endpoints for routine application within the clinical setting. Particular focus is given to the biochemistry of the mitochondria influencing each endpoint and the relation of these to toxicity. Current approaches such as the use of metabolic markers (e.g. lactate production), and muscle biopsies to measure mitochondrial proteins were found to lack specificity. Newly emerging identified endpoints were: fibroblast growth factor-21, glucose uptake, mitochondrial membrane potential, mitochondrial morphology, mtDNA heteroplasmy, and mutation of mtDNA and nuclear DNA. Owed to the advancement in genetic analysis techniques, it is suggested by this review that genotypic endpoints of mtDNA mutation and heteroplasmy show particular promise as indicators of mitochondrial disease. It is, however, acknowledged that any single endpoint in isolation offers limited information; therefore, it is recommended that analysis of several endpoints simultaneously will offer the greatest benefit in terms of disease diagnosis and study. It is hoped that this review further highlights the need for advancement in understanding mitochondrial disease.
Topics: Humans; DNA, Mitochondrial; Mitochondrial Diseases; Mitochondria; Mutation; Genotype
PubMed: 37144479
DOI: 10.1093/mutage/gead010