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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 -
Developmental Neurobiology Jul 2020The formation of axons and dendrites during development, and their regeneration following injury, are energy intensive processes. The underlying assembly and dynamics of... (Review)
Review
The formation of axons and dendrites during development, and their regeneration following injury, are energy intensive processes. The underlying assembly and dynamics of the cytoskeleton, axonal transport mechanisms, and extensive signaling networks all rely on ATP and GTP consumption. Cellular ATP is generated through oxidative phosphorylation (OxP) in mitochondria, glycolysis and "regenerative" kinase systems. Recent investigations have focused on the role of the mitochondrion in axonal development and regeneration emphasizing the importance of this organelle and OxP in axon development and regeneration. In contrast, the understanding of alternative sources of ATP in neuronal morphogenesis and regeneration remains largely unexplored. This review focuses on the current state of the field of neuronal bioenergetics underlying morphogenesis and regeneration and considers the literature on the bioenergetics of non-neuronal cell motility to emphasize the potential contributions of non-mitochondrial energy sources.
Topics: Animals; Axons; Energy Metabolism; Humans; Mitochondria; Morphogenesis; Nerve Regeneration; Neurons
PubMed: 32750228
DOI: 10.1002/dneu.22776 -
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 -
Toxicology Nov 2017There are approximately 1500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al., 2006).... (Review)
Review
There are approximately 1500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al., 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.
Topics: Animals; DNA Damage; DNA, Mitochondrial; Ecotoxicology; Environmental Exposure; Environmental Pollutants; Gene-Environment Interaction; Genomic Instability; Humans; Mitochondria; Risk Assessment
PubMed: 28756246
DOI: 10.1016/j.tox.2017.07.014 -
The Journal of Toxicological Sciences 2021Pb exposure is a worldwide environmental contamination issue which has been of concern to more and more people. Exposure to environmental Pb and its compounds through... (Review)
Review
Pb exposure is a worldwide environmental contamination issue which has been of concern to more and more people. Exposure to environmental Pb and its compounds through food and respiratory routes causes toxic damage to the digestive, respiratory, cardiovascular and nervous systems, etc. Children and pregnant women are particularly vulnerable to Pb. Pb exposure significantly destroys children's learning ability, intelligence and perception ability. Mitochondria are involved in various life processes of eukaryotes and are one of the most sensitive organelles to various injuries. There is no doubt that Pb-induced mitochondrial damage can widely affect various physiological processes and cause great harm. In this review, we summarized the toxic effects of Pb on mitochondria which led to various pathological processes. Pb induces mitochondrial dysfunction leading to the increased level of oxidative stress. In addition, Pb leads to cell apoptosis via mitochondrial permeability transition pore (MPTP) opening. Also, Pb can stimulate the development of mitochondria-mediated inflammatory responses. Furthermore, Pb triggers the germination of autophagy via the mitochondrial pathway and induces mitochondrial dysfunction, disturbing intracellular calcium homeostasis. In a word, we discussed the effects of Pb exposure on mitochondria, hoping to provide some references for further research and better therapeutic options for Pb exposure.
Topics: Apoptosis; Autophagy; Calcium; Child; Child, Preschool; Environmental Exposure; Environmental Pollutants; Female; Homeostasis; Humans; Inflammation; Lead; Male; Mitochondria; Mitochondrial Permeability Transition Pore; Oxidative Stress; Pregnancy
PubMed: 34334556
DOI: 10.2131/jts.46.345 -
Mitochondrion Nov 2018Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A... (Review)
Review
Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A small clinical trial published in 2017 suggests this is possible. Based on a new unifying theory of pathogenesis for autism called the cell danger response (CDR) hypothesis, this study of 10 boys, ages 5-14years, showed that all 5 boys who received antipurinergic therapy (APT) with a single intravenous dose of suramin experienced improvements in all the core symptoms of autism that lasted for 5-8weeks. Language, social interaction, restricted interests, and repetitive movements all improved. Two children who were non-verbal spoke their first sentences. None of these improvements were observed in the placebo group. Larger and longer studies are needed to confirm this promising discovery. This review introduces the concept of M2 (anti-inflammatory) and M1 (pro-inflammatory) mitochondria that are polarized along a functional continuum according to cell stress. The pathophysiology of the CDR, the complementary functions of M1 and M2 mitochondria, relevant gene-environment interactions, and the metabolic underpinnings of behavior are discussed as foundation stones for understanding the improvements in ASD behaviors produced by antipurinergic therapy in this small clinical trial.
Topics: Administration, Intravenous; Adolescent; Autistic Disorder; Child; Child, Preschool; Clinical Trials as Topic; Humans; Male; Mitochondria; Placebos; Purinergic Antagonists; Suramin; Treatment Outcome
PubMed: 29253638
DOI: 10.1016/j.mito.2017.12.007