Degradation of ATFS-1 by LONP-1 promotes deleterious mitochondrial genome heteroplasmy

The accumulation of deleterious mitochondrial genomes (ΔmtDNAs) underlies inherited mitochondrial diseases and contributes to the aging-associated decline in mitochondrial function. Heteroplasmy occurs when a ΔmtDNA expands, ultimately causing a decline in oxidative phosphorylation (OXPHOS) function. In response to mitochondrial perturbations, the transcription factor ATFS-1 induces a transcription program to promote cell survival and recovery of mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ΔmtDNAs in heteroplasmic worms. However, the mechanism(s) by which ATFS-1 promotes ΔmtDNA propagation relative to wild-type mtDNAs is unclear. Here, we show that mitochondrial-localized ATFS-1 binds almost exclusively to ΔmtDNAs in heteroplasmic worms and promotes binding of the mtDNA replicative polymerase (POLG). Interestingly, inhibition of the mtDNA-bound protease LONP-1 caused ATFS-1 and POLG to bind equally to ΔmtDNAs and wild-type mtDNAs. Furthermore, LONP-1 inhibition in C. elegans and human cybrid cells improved the heteroplasmy ratio and restored OXPHOS function. Our findings suggest that degradation of ATFS-1 within functional mitochondria by LONP-1 establishes the enriched interaction between ATFS-1 and ΔmtDNAs required to maintain heteroplasmy.