LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.

Abstract

The accumulation of deleterious mitochondrial DNA (ΔmtDNA) causes inherited mitochondrial diseases and aging-associated decline in mitochondrial functions such as oxidative phosphorylation (OXPHOS) function. Upon mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcription program to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ΔmtDNAs in heteroplasmic worms. The mechanism(s) by which ATFS-1 promotes ΔmtDNA accumulation relative to wildtype mtDNAs is unclear. Here, we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria due to degradation by the mtDNA-bound protease LONP-1, resulting in the nearly exclusive association between ATFS-1 and ΔmtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to ΔmtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wildtype mtDNAs. LONP-1 inhibition in C. elegans and human cybrid cells improved the heteroplasmy ratio and restored OXPHOS. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1.