Mitochondrial Genome Maintenance: Damage and Repair Pathways

Abstract

The mitochondrial genomic material (mtDNA), similarly to nuclear genome, is exposed to a plethora of exogenous and endogenous agents, as well as natural processes like replication that compromise the integrity and fidelity of the mtDNA, despite the abovementioned, the mtDNA does not contain genes involved in DNA repair, therefore mitochondria completely depend on the importation of nuclear-encoded elements to achieve genome maintenance, which implies a coordinated crosstalk between these two organelles. It has been determined that to counteract damage, mitochondria possess well-defined repair pathways quite similar to those of the nucleus, among which are: base excision repair (BER), mismatch repair (MMR), single-strand break repair (SSBR), microhomology-mediated end joining (MMEJ), and probably homology recombination dependent repair (HRR). If these repair pathways are nonfunctional and the lesions remain unrepaired, the emergence of mutations, deletions, and other insults may result in compromised cellular viability and disease.

First record of a tandem-repeat region within the mitochondrial genome of Clonorchis sinensis using a long-read sequencing approach

“…In response to this stress, replication of the mitochondrial genome might need to be highly efficient, in order to have a high number of genomes in the cell at any one time. This might avoid harmful mutations in the mitochondrial genome by increasing the number of template molecules in each cell, required to repair DNA in the least error-prone way [58,67,68]. A large number of genomes might act also as a 'buffer' in the cell-even if some get damaged, many functionally intact genomes will be present, ensuring that replication and transcription of mitochondrial genes are not disrupted within the cell.…”

The Similarities between Human Mitochondria and Bacteria in the Context of Structure, Genome, and Base Excision Repair System

“…The evidence is still limited, but some studies show that repair proteins are imported to mitochondria only in response to stress signals [155]. It is believed that the BER system has a bacterial origin, as the organelle itself [124]. Hence, the next chapter describes human mitochondrial and bacterial BER proteins and stresses their homology and overlapping functions.…”

“…MtDNA is highly sensitive to oxidative lesions; therefore, the mutagenesis rate in mtDNA may be even 10 to 20-fold higher than in nDNA [78,124]. The mtDNA seems to be an easy target for the free radicals due to a lack of chromatin structure (protection of histones).…”

“…Homologous recombination (HR) is essential for mtDNA repair in plants and yeast, but it is not confirmed to operate in human mitochondria. In addition, nucleotide excision repair (NER) action is not identified in mitochondria [124]. BER is recognized as a predominant system in mitochondria and repairs lesions resulting from oxidation, deamination, alkylation, and SSBs [78].…”

“…The BER system is highly conserved throughout all organisms [124]. Bacterial DNA repair systems differ according to the species of bacteria and are dependent on the environment they inhabit [163].…”