Mitochondrial DNA Instability in Mammalian Cells

• Published in: Antioxidants & redox signaling Vol. 36; no. 13-15; p. 885
• Main Authors: Carvalho, Gustavo, Repolês, Bruno Marçal, Mendes, Isabela, Wanrooij, Paulina H
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• Subjects: Animals; Cytosol - metabolism; DNA Damage; DNA Repair; DNA Replication; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Mammals - genetics; Mammals - metabolism; Mitochondria - metabolism; genome instability; DNA replication; mitochondrial DNA
• ISSN: 1557-7716
• DOI: 10.1089/ars.2021.0091

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. 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. 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? 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. . 36, 885-905.