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Experimental & Molecular Medicine Mar 2023In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS... (Review)
Review
In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin. In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.
Topics: Humans; DNA, Mitochondrial; Immunity, Innate; Inflammasomes; Inflammation; Mitochondria; Nucleotidyltransferases; Signal Transduction; Membrane Proteins
PubMed: 36964253
DOI: 10.1038/s12276-023-00965-7 -
Annual Review of Biochemistry Jun 2023According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16... (Review)
Review
According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.
Topics: Animals; Humans; DNA, Mitochondrial; Mitochondria; Immunity, Innate; Aging; Cell Nucleus; Mammals
PubMed: 37001140
DOI: 10.1146/annurev-biochem-032620-104401 -
International Journal of Molecular... Apr 2021Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly... (Review)
Review
Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.
Topics: Animals; DNA Methylation; DNA Replication; DNA, Mitochondrial; Epigenesis, Genetic; Gene Expression Regulation; Genome, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Protein Processing, Post-Translational
PubMed: 33925624
DOI: 10.3390/ijms22094594 -
FEBS Letters Apr 2021In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and... (Review)
Review
In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and fusion, as well as distribution along cytoskeletal tracks, are counterbalancing mechanisms acting in concert to maintain a mitochondrial network tuned to cellular function. Balanced mitochondrial dynamics permits quality control of the network including biogenesis and turnover, and distribution of mitochondrial DNA, and is linked to metabolic status. Cellular and organismal health relies on a delicate balance between fission and fusion, and large rearrangements in the mitochondrial network can be seen in response to cellular insults and disease. Indeed, dysfunction in the major components of the fission and fusion machineries including dynamin-related protein 1 (DRP1), mitofusins 1 and 2 (MFN1, MFN2) and optic atrophy protein 1 (OPA1) and ensuing imbalance of mitochondrial dynamics can lead to neurodegenerative disease. Altered mitochondrial dynamics is also seen in more common diseases. In this review, the machinery involved in mitochondrial dynamics and their dysfunction in disease will be discussed.
Topics: Animals; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neurodegenerative Diseases
PubMed: 33742459
DOI: 10.1002/1873-3468.14077 -
Cell Reports Dec 2022Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation...
Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the FF-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
Topics: Humans; Animals; Mice; DNA, Mitochondrial
PubMed: 36476853
DOI: 10.1016/j.celrep.2022.111774 -
The Journal of Biological Chemistry Dec 2020Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and... (Review)
Review
Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The re-constituted transcriptional complexes of (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.
Topics: DNA, Mitochondrial; Gene Expression Regulation; Humans; Mitochondrial Proteins; Transcription Factors; Transcription Initiation Site; Transcription, Genetic
PubMed: 33127643
DOI: 10.1074/jbc.REV120.011202 -
Nucleic Acids Research Nov 2020Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span... (Review)
Review
Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span kilobases in length and the loss of these associated genes contributes to crippled oxidative phosphorylation and overall decline in mitochondrial fitness. There is not a united view for how mtDNA deletions are generated and the molecular mechanisms underlying this process are poorly understood. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We propose that while erroneous replication and repair can separately contribute to deletion formation, crosstalk between these pathways is also involved in generating deletions.
Topics: DNA Breaks, Double-Stranded; DNA Mismatch Repair; DNA Repair; DNA Replication; DNA, Mitochondrial; Genetic Diseases, Inborn; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation; Sequence Deletion
PubMed: 33021629
DOI: 10.1093/nar/gkaa804 -
Ageing Research Reviews Nov 2020Mitochondrial dysfunction is one of the hallmarks of aging. Consistently mitochondrial DNA (mtDNA) copy number and function decline with age in various tissues. There is... (Review)
Review
Mitochondrial dysfunction is one of the hallmarks of aging. Consistently mitochondrial DNA (mtDNA) copy number and function decline with age in various tissues. There is increasing evidence to support that mitochondrial dysfunction drives ovarian aging. A decreased mtDNA copy number is also reported during ovarian aging. However, the mitochondrial mechanisms contributing to ovarian aging and infertility are not fully understood. Additionally, investigations into mitochondrial therapies to rejuvenate oocyte quality, select viable embryos and improve mitochondrial function may help enhance fertility or extend reproductive longevity in the future. These therapies include the use of mitochondrial replacement techniques, quantification of mtDNA copy number, and various pharmacologic and lifestyle measures. This review aims to describe the key evidence and current knowledge of the role of mitochondria in ovarian aging and identify the emerging potential options for therapy to extend reproductive longevity and improve fertility.
Topics: Aging; DNA, Mitochondrial; Humans; Longevity; Mitochondria; Oocytes
PubMed: 32896666
DOI: 10.1016/j.arr.2020.101168 -
Cellular & Molecular Immunology Dec 2023Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING... (Review)
Review
Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.
Topics: Humans; DNA, Mitochondrial; Signal Transduction; Immunity, Innate; Nucleotidyltransferases; Mitochondria; Autoimmune Diseases; Neoplasms
PubMed: 37932533
DOI: 10.1038/s41423-023-01086-x -
Mitochondrion Sep 2021There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the... (Review)
Review
There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). It has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis is a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific value around the investigation of blood mtDNAcn.
Topics: DNA Copy Number Variations; DNA, Mitochondrial; Humans; Mitochondria
PubMed: 34157430
DOI: 10.1016/j.mito.2021.06.010