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Mitochondrion Jan 2022Iron-sulfur clusters (ISCs) are highly conserved moieties embedded into numerous crucial proteins in almost all bacteria, plants and mammals. As such, ISC biosynthesis... (Review)
Review
Iron-sulfur clusters (ISCs) are highly conserved moieties embedded into numerous crucial proteins in almost all bacteria, plants and mammals. As such, ISC biosynthesis is critical to cellular function. The pathway was first characterized in bacteria by the late 1990s, and over the subsequent 20 years there has been increasing understanding of its components in humans. Defects in the ISC pathway are now associated with many different human disease states, such as Friedreich ataxia and ISCU myopathy. Whilst the disorders have variable clinical features, most involve neurological phenotypes. There are common biochemical signatures in most of these conditions, as a lack of ISCs causes deficiencies of target proteins including Complex I, II and III, aconitase and lipoic acid. This review focuses on the disorders of ISC biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features will be discussed, providing a reference point for clinicians diagnosing and managing these patients. Therapies are mostly supportive at this stage. However, the improved understanding of the pathophysiology of these conditions could pave the way for disease-modifying therapies in the near future.
Topics: Animals; Central Nervous System Diseases; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Iron-Sulfur Proteins; Mitochondria
PubMed: 34687937
DOI: 10.1016/j.mito.2021.10.004 -
Mitochondrion Jul 2018Mitochondria are intracellular organelles that originate from a bacterial symbiont, and they retain multiple features of this bacterial ancestry. The immune system... (Review)
Review
Mitochondria are intracellular organelles that originate from a bacterial symbiont, and they retain multiple features of this bacterial ancestry. The immune system evolved to detect the presence of invading pathogens, including bacteria, to eliminate them by a diversity of antimicrobial mechanisms and to mount long-term protective immunity. Due to their bacterial ancestry, mitochondria are sensed by the innate immune system, and trigger inflammatory responses comparable to those induced by pathogenic bacteria. In both cases, innate sensing mechanisms involve Toll-Like Receptors, Formyl Peptide Receptors, inflammasomes or the cGAS/STING pathway. Stressed mitochondria release mitochondrial molecules, such as cardiolipin and mitochondrial DNA, which are sensed as cellular damage potentially caused by infections. Recent research has identified several conditions in which mitochondrial stress-induced immunity is essential to effective antimicrobial defenses. But, in pathological conditions, the abnormal activation of the innate immune system by damaged mitochondria results in auto-inflammatory or autoimmune diseases. To prevent undesirable mitochondria-targeted responses, immune tolerance toward mitochondria must be established, involving regulation of mitophagy and mitochondrial permeability, as well as activation of specific nucleases and pro-apoptotic caspases. Overall, recent findings identify mitochondria as central in the induction of innate immunity, and provide new insights as to how immune responses to these multi-functional organelles might be exploited therapeutically in various disease states.
Topics: Animals; Cytokines; Humans; Immunity, Innate; Inflammasomes; Inflammation Mediators; Metabolic Diseases; Mitochondria
PubMed: 29054471
DOI: 10.1016/j.mito.2017.10.007 -
Cell Reports Dec 2022Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA)...
Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPR), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPR in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Genome, Mitochondrial; DNA, Mitochondrial; Mitochondria; Unfolded Protein Response
PubMed: 36577367
DOI: 10.1016/j.celrep.2022.111875 -
Mitochondrion Mar 2020
Topics: Energy Metabolism; Homeostasis; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 31917323
DOI: 10.1016/j.mito.2019.12.007 -
Mitochondrion May 2022Mitochondria are essential for neuronal survival and mitochondrial dysfunction is a hallmark of neurodegeneration. The loss in mitochondrial energy production, oxidative...
Mitochondria are essential for neuronal survival and mitochondrial dysfunction is a hallmark of neurodegeneration. The loss in mitochondrial energy production, oxidative stress, and changes in calcium handling are associated with neurodegenerative diseases; however, different sites and types of mitochondrial dysfunction are linked to distinct neuropathologies. Understanding the causal or correlative relationship between changes in mitochondria and neuropathology will lead to new therapeutic strategies. Here, we summarize the evidence of site-specific mitochondrial dysfunction and mitochondrial-related clinical trials for neurodegenerative diseases. We further discuss potential therapeutic approaches, such as mitochondrial transplantation, restoration of mitochondrial function, and pharmacological alleviation of mitochondrial dysfunction.
Topics: Calcium; Humans; Mitochondria; Neurodegenerative Diseases; Oxidative Stress
PubMed: 35182728
DOI: 10.1016/j.mito.2022.02.004 -
Mitochondrion Mar 2021Early-life adversity (ELA), which includes maltreatment, neglect, or severe trauma in childhood, increases the life-long risk for negative health outcomes. Mitochondria...
Early-life adversity (ELA), which includes maltreatment, neglect, or severe trauma in childhood, increases the life-long risk for negative health outcomes. Mitochondria play a key role in the stress response and may be an important mechanism by which stress is transduced into biological risk for disease. By responding to cues from stress-signaling pathways, mitochondria interact dynamically with physiological stress responses coordinated by the central nervous, endocrine, and immune systems. Preclinical evidence suggests that alterations in mitochondrial function and structure are linked to both early stress and systemic biological dysfunction. Early clinical studies support that increased mitochondrial DNA content and altered cellular energy demands may be present in individuals with a history of ELA. Further research should investigate mitochondria as a potential therapeutic target following ELA.
Topics: Adverse Childhood Experiences; Animals; Central Nervous System; Endocrine System; Humans; Immune System; Mitochondria; Stress, Physiological
PubMed: 33484871
DOI: 10.1016/j.mito.2021.01.005 -
Cellular and Molecular Life Sciences :... Nov 2017Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine,... (Review)
Review
Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin's protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.
Topics: Animals; Antioxidants; Humans; Melatonin; Mitochondria; Reperfusion Injury
PubMed: 28795196
DOI: 10.1007/s00018-017-2618-6 -
Mitochondrion May 2020While in heterotrophic cells and in darkness mitochondria serve as main producers of energy, during photosynthesis this function is transferred to chloroplasts and the... (Review)
Review
While in heterotrophic cells and in darkness mitochondria serve as main producers of energy, during photosynthesis this function is transferred to chloroplasts and the main role of mitochondria in bioenergetics turns to be the balance of the level of phosphorylation of adenylates and of reduction of pyridine nucleotides to avoid over-energization of the cell and optimize major metabolic fluxes. This is achieved via the establishment and regulation of local equilibria of the tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase and fumarase in one branch and aconitase and isocitrate dehydrogenase in another branch. In the conditions of elevation of redox level, the TCA cycle is transformed into a non-cyclic open structure (hemicycle) leading to the export of the tricarboxylic acid (citrate) to the cytosol and to the accumulation of the dicarboxylic acids (malate and fumarate). While the buildup of NADPH in chloroplasts provides operation of the malate valve leading to establishment of NADH/NAD ratios in different cell compartments, the production of NADH by mitochondria drives citrate export by establishing conditions for the operation of the citrate valve. The latter regulates the intercompartmental NADPH/NADP ratio and contributes to the biosynthesis of amino acids and other metabolic products during photosynthesis.
Topics: Amino Acids; Citric Acid; Citric Acid Cycle; Mitochondria; Photosynthesis; Plant Physiological Phenomena; Plants
PubMed: 32278088
DOI: 10.1016/j.mito.2020.04.003 -
Open Biology Oct 2021The recently developed ultrastructure expansion microscopy (U-ExM) technique allows us to increase the spatial resolution within a cell or tissue for microscopic imaging...
The recently developed ultrastructure expansion microscopy (U-ExM) technique allows us to increase the spatial resolution within a cell or tissue for microscopic imaging through the physical expansion of the sample. In this study, we validate the use of U-ExM in measuring the expansion factors of several different compartments/organelles and thus verify the isotropic expansion of the cell. We furthermore demonstrate the use of this sample preparation protocol for future studies by visualizing the nucleus and kDNA, as well as proteins of the cytoskeleton, the basal body, the mitochondrion and the endoplasmic reticulum. Lastly, we discuss the challenges and opportunities of U-ExM.
Topics: Cell Nucleus; DNA, Kinetoplast; Microscopy, Fluorescence; Microtubules; Mitochondria; Protozoan Proteins; Trypanosoma brucei brucei
PubMed: 34637654
DOI: 10.1098/rsob.210132 -
Journal of Inherited Metabolic Disease Jul 2015Mitochondrial diseases are clinically, biochemically and genetically heterogeneous disorders of two genomes, for which effective curative therapies are currently... (Review)
Review
Mitochondrial diseases are clinically, biochemically and genetically heterogeneous disorders of two genomes, for which effective curative therapies are currently lacking. With the exception of a few rare vitamin/cofactor responsive conditions (including ACAD9 deficiency, disorders of coenzyme Q(10) biosynthesis, and Leigh syndrome caused by mutations in the SLC19A3 transporter), the mainstay of treatment for the vast majority of patients involves supportive measures. The search for a cure for mitochondrial disease is the subject of intensive research efforts by many investigators across the globe, but the goal remains elusive. The clinical and genetic heterogeneity, multisystemic nature of many of these disorders, unpredictable natural course, relative inaccessibility of the mitochondrion and lack of validated, clinically meaningful outcome measures, have all presented great challenges to the design of rigorous clinical trials. This review discusses barriers to developing effective therapies for mitochondrial disease, models for evaluating the efficacy of novel treatments and summarises the most promising emerging therapies in six key areas: 1) antioxidant approaches; 2) stimulating mitochondrial biogenesis; 3) targeting mitochondrial membrane lipids, dynamics and mitophagy; 4) replacement therapy; 5) cell-based therapies; and 6) gene therapy approaches for both mtDNA and nuclear-encoded defects of mitochondrial metabolism.
Topics: Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Organelle Biogenesis
PubMed: 25962587
DOI: 10.1007/s10545-015-9855-3