Mitochondrial DNA Instability in Mammalian Cells

Abstract

Significance: The small, multicopy mitochondrial genome (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.

Current Progress of Mitochondrial Genome Editing by CRISPR

“…For clinical applications that target mtDNA disorder, it is essential to achieve homoplasmic status in a cell by eliminating the mutated mtDNA. In contrast to nuclear DNA (nDNA) repair pathways, the efficient DNA double-strand break (DSB) repair and homologous recombination (HR) mechanisms are lacking in mammalian mitochondria ( Nissanka et al, 2019 ; Carvalho et al, 2021 ). Once cut on both strands, mtDNA molecules are not repaired, which results in rapid degradation of mtDNA in mammalian cells ( Peeva et al, 2018 ).…”

Building the case for mitochondrial transplantation as an anti-aging cardiovascular therapy

“…In essence, depending on the burden of damage present within mitochondria, DNA polymerase γ can either facilitate the retention of healthy mtDNA or further aggrandize mito-dysfunction ( 69 ). Importantly, regardless of the cause of mtDNA damage, damaged mtDNA that escapes from the mitochondria into the cytosol can activate inflammatory responses, via TLR9, cGas-STING, and NLRP3 inflammasome signaling ( 70 , 71 ). Chronic activation of these cellular responses contributes to the sterile inflammation seen in aging ( 70 ).…”

Genomic Changes Driven by Radiation-Induced DNA Damage and Microgravity in Human Cells

“…The presence of MMR proteins has been reported in mammalian mitochondria, but the activity of this pathway remains elu- Mitochondrial DNA (mtDNA) is also damaged by the direct and indirect action of radiation and it undergoes repair, although mtDNA repair mechanisms are less characterized. Evidence has shown that BER activity, carried out by the same proteins active in the nucleus, is also predominant in mitochondria to repair oxidized bases and AP sites [62]. Mammalian mitochondria also contain proteins for nucleotide excision repair (NER), the NHEJ and HR repair pathways, but the repair activities of these pathways are not clearly demonstrated and are still under investigation.…”