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Mitochondrial DNA Instability in Mammalian Cells
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-3827-4619
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0001-5704-3093
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-8607-7564
2022 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 36, no 13-15, p. 885-905Article, review/survey (Refereed) Published
Abstract [en]

Significance: The small, multicopy mitochondrial genome (mitochondrial DNA [mtDNA]) is essential for efficient energy production, as alterations in its coding information or a decrease in its copy number disrupt mitochondrial ATP synthesis. However, the mitochondrial replication machinery encounters numerous challenges that may limit its ability to duplicate this important genome and that jeopardize mtDNA stability, including various lesions in the DNA template, topological stress, and an insufficient nucleotide supply.

Recent Advances: An ever-growing array of DNA repair or maintenance factors are being reported to localize to the mitochondria. We review current knowledge regarding the mitochondrial factors that may contribute to the tolerance or repair of various types of changes in the mitochondrial genome, such as base damage, incorporated ribonucleotides, and strand breaks. We also discuss the newly discovered link between mtDNA instability and activation of the innate immune response.

Critical Issues: By which mechanisms do mitochondria respond to challenges that threaten mtDNA maintenance? What types of mtDNA damage are repaired, and when are the affected molecules degraded instead? And, finally, which forms of mtDNA instability trigger an immune response, and how?

Future Directions: Further work is required to understand the contribution of the DNA repair and damage-tolerance factors present in the mitochondrial compartment, as well as the balance between mtDNA repair and degradation. Finally, efforts to understand the events underlying mtDNA release into the cytosol are warranted. Pursuing these and many related avenues can improve our understanding of what goes wrong in mitochondrial disease.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2022. Vol. 36, no 13-15, p. 885-905
Keywords [en]
mitochondrial DNA, genome instability, DNA replication
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-187332DOI: 10.1089/ars.2021.0091ISI: 000669978100001PubMedID: 34015960Scopus ID: 2-s2.0-85130003932OAI: oai:DiVA.org:umu-187332DiVA, id: diva2:1592241
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Society for Medical Research (SSMF)Åke Wiberg FoundationAvailable from: 2021-09-08 Created: 2021-09-08 Last updated: 2022-06-09Bibliographically approved

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Carvalho, GustavoRepolês, Bruno MarçalMendes, IsabelaWanrooij, Paulina H.

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