Abstract
Mitochondria are highly specialised organelles required for key cellular processes including ATP production through cellular respiration and controlling cell death via apoptosis. Unlike other organelles, mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function – deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular ageing and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear-encoded DNA repair proteins that are translocated into the mitochondria.Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.
Highlights
Mitochondria are highly specialised and dynamic organelles required for fundamental cellular processes including ATP generation via oxidative phosphorylation during cellular respiration and the control of programmed cell death by apoptosis
Significant strides have been made to identify and characterise the mechanisms that protect the integrity of the mitochondrial genome
This expanded portfolio of mechanisms comprising at least BER, microhomology-mediated end joining (MMEJ), translesion synthesis (TLS), mismatch repair (MMR) with emerging evidence for homologous recombination (HR) and HR mediated restart of stalled mitochondrial replication [41,42,63,96,117]. This suggests that mammalian mitochondria are better equipped than previously thought to tolerate and repair the high levels of damaging agents they are exposed to through cellular respiration [37]
Summary
Mitochondria are highly specialised and dynamic organelles required for fundamental cellular processes including ATP generation via oxidative phosphorylation during cellular respiration and the control of programmed cell death by apoptosis (reviewed in [1]). Significant strides have been made to identify and characterise the mechanisms that protect the integrity of the mitochondrial genome.
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