Mechanisms of Mitochondrial DNA Deletion Formation.

Mitochondrial DNA (mtDNA) encodes a subset of genes which are essential for oxidative phosphorylation. Deletions in the mtDNA can ablate a number of these genes and result in mitochondrial dysfunction, which is associated with bona fide mitochondrial disorders. Although mtDNA deletions are thought to occur as a result of replication errors or following double-strand breaks, the exact mechanism(s) behind deletion formation have yet to be determined. In this review we discuss the current knowledge about the fate of mtDNA following double-strand breaks, including the molecular players which mediate the degradation of linear mtDNA fragments and possible mechanisms of recircularization. We propose that mtDNA deletions formed from replication errors versus following double-strand breaks can be mediated by separate pathways.We are grateful for support from the National Institutes of Health Grants 1R01AG036871, 5R01EY010804, and 1R01NS079965, the Muscular Dystrophy Association and the Champ Foundation (to C.T.M.); and the Medical Research Council Grant MC_UU_00015/4 (to M.M.)