Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial UPR

Mitochondrial genomes (mtDNA) encode essential oxidative phosphorylation (OxPhos) components. Because hundreds of mtDNAs exist per cell, the presence of a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OxPhos declines resulting in cellular dysfunction. For example, Kearns-Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells(1) and dopamine neurons(2) during aging. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OxPhos dysfunction is by activating the mitochondrial unfolded protein response (UPR(mt)), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria(3,4). Here, we investigated the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic C. elegans strain that stably harbors wildtype mtDNA and mtDNA with a 3.1 kilobase deletion (ΔmtDNA) lacking four essential genes(5). The heteroplasmic strain, which has 60% ΔmtDNA, displayed modest mitochondrial dysfunction and constitutive UPR(mt) activation. Impressively, ATFS-1 impairment reduced the ΔmtDNA 10-fold, reducing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPR(mt) activation caused by OxPhos defects propagates or maintains the deleterious mtDNA in an attempt to recover OxPhos activity by promoting mitochondrial biogenesis and dynamics.