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Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.Biochimica Et Biophysica Acta.... Jun 2022Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle... (Review)
Review
Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
Topics: DNA Replication; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Phenotype
PubMed: 35341749
DOI: 10.1016/j.bbabio.2022.148554 -
Cold Spring Harbor Perspectives in... Jul 2019Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis... (Review)
Review
Mitochondria are metabolic hubs that use multiple proteases to maintain proteostasis and to preserve their overall quality. A decline of mitochondrial proteolysis promotes cellular stress and may contribute to the aging process. Mitochondrial proteases have also emerged as tightly regulated enzymes required to support the remarkable mitochondrial plasticity necessary for metabolic adaptation in a number of physiological scenarios. Indeed, the mutation and dysfunction of several mitochondrial proteases can cause specific human diseases with severe metabolic phenotypes. Here, we present an overview of the proteolytic regulation of key mitochondrial functions such as respiration, lipid biosynthesis, and mitochondrial dynamics, all of which are required for metabolic control. We also pay attention to how mitochondrial proteases are acutely regulated in response to cellular stressors or changes in growth conditions, a greater understanding of which may one day uncover their therapeutic potential.
Topics: DNA, Mitochondrial; Gene Expression Regulation, Enzymologic; Genome, Mitochondrial; Peptide Hydrolases; Proteins
PubMed: 30670467
DOI: 10.1101/cshperspect.a033936 -
International Journal of Molecular... Sep 2022Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that... (Review)
Review
Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.
Topics: Adenosine Triphosphate; DNA Damage; DNA Repair; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Neurodegenerative Diseases; Reactive Oxygen Species
PubMed: 36232693
DOI: 10.3390/ijms231911391 -
Cells Feb 2022Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of... (Review)
Review
Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
Topics: DNA, Mitochondrial; Humans; Inflammation; Mitochondria; Mitochondrial Membranes
PubMed: 35203322
DOI: 10.3390/cells11040675 -
Biochimica Et Biophysica Acta Nov 2015Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered... (Review)
Review
Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Topics: Animals; DNA Damage; DNA Replication; DNA, Mitochondrial; Free Radicals; Humans; Mutation
PubMed: 26050972
DOI: 10.1016/j.bbabio.2015.06.001 -
Molecular Genetics and Metabolism 2022Mitochondrial DNA (mtDNA) replication depends on the mitochondrial import of hundreds of nuclear encoded proteins that control the mitochondrial genome maintenance and... (Review)
Review
Mitochondrial DNA (mtDNA) replication depends on the mitochondrial import of hundreds of nuclear encoded proteins that control the mitochondrial genome maintenance and integrity. Defects in these processes result in an expanding group of disorders called mtDNA maintenance defects that are characterized by mtDNA depletion and/or multiple mtDNA deletions with variable phenotypic manifestations. As it applies for mitochondrial disorders in general, current treatment options for mtDNA maintenance defects are limited. Lately, with the development of model organisms, improved understanding of the pathophysiology of these disorders, and a better knowledge of their natural history, the number of preclinical studies and existing and planned clinical trials has been increasing. In this review, we discuss recent preclinical studies and current and future clinical trials concerning potential therapeutic options for the different mtDNA maintenance defects.
Topics: Humans; DNA, Mitochondrial; Mitochondria; Mitochondrial Diseases
PubMed: 35914366
DOI: 10.1016/j.ymgme.2022.07.003 -
Current Heart Failure Reports Feb 2023We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy. (Review)
Review
PURPOSE OF REVIEW
We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy.
RECENT FINDINGS
Mechanistic studies have shed light into the underpinnings of mitochondrial disorders, providing novel insights into mitochondrial physiology and identifying new therapeutic targets. Mitochondrial disorders are a group of rare genetic diseases that are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes that are essential to mitochondrial function. The clinical picture is extremely heterogeneous, the onset can occur at any age, and virtually, any organ or tissue can be involved. Since the heart relies primarily on mitochondrial oxidative metabolism to fuel contraction and relaxation, cardiac involvement is common in mitochondrial disorders and often represents a major determinant of their prognosis.
Topics: Humans; Heart Failure; Mitochondrial Diseases; DNA, Mitochondrial; Cardiomyopathies; Mutation
PubMed: 36802007
DOI: 10.1007/s11897-023-00592-3 -
Chemical Research in Toxicology Oct 2020Mitochondria have a plethora of functions within a eukaryotic cell, ranging from energy production, cell signaling, and protein cofactor synthesis to various aspects of... (Review)
Review
Mitochondria have a plethora of functions within a eukaryotic cell, ranging from energy production, cell signaling, and protein cofactor synthesis to various aspects of metabolism. Mitochondrial dysfunction is known to cause over 200 named disorders and has been implicated in many human diseases and aging. Mitochondria have their own genetic material, mitochondrial DNA (mtDNA), which encodes 13 protein subunits in the oxidative phosphorylation system and a full set of transfer and rRNAs. Although more than 99% of the proteins in mitochondria are nuclear DNA (nDNA)-encoded, the integrity of mtDNA is critical for mitochondrial functions, as evidenced by mitochondrial diseases sourced from mtDNA mutations and depletions and the vital role of fragmented mtDNA molecules in cell signaling pathways. Previous research has shown that mtDNA is an important target of genotoxic assaults by a variety of chemical and physical factors. This Perspective discusses the prevalence of mtDNA damage by comparing the abundance of lesions in mDNA and nDNA and summarizes current knowledge on the biological pathways to cope with mtDNA damage, including mtDNA repair, mtDNA degradation, and mitochondrial fission and fusion. Also, emerging roles of mtDNA damage in mutagenesis and immune responses are reviewed.
Topics: Animals; DNA Damage; DNA, Mitochondrial; Humans
PubMed: 32486637
DOI: 10.1021/acs.chemrestox.0c00083 -
Nature Communications Aug 2023The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not...
The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
Topics: Male; Mice; Animals; Mitochondria; DNA, Mitochondrial; Brain; Phenotype
PubMed: 37563104
DOI: 10.1038/s41467-023-39941-0 -
Experimental Gerontology Jul 2023Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous... (Review)
Review
Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.
Topics: Animals; Humans; DNA Copy Number Variations; DNA, Mitochondrial; Mutation; Aging; Neoplasms
PubMed: 37172915
DOI: 10.1016/j.exger.2023.112203