Journal
NATURE CELL BIOLOGY
Volume 24, Issue 2, Pages 181-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-021-00840-5
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Funding
- NIH Office of Research 362 Infrastructure Programs [P40 OD010440]
- HHMI
- Mallinckrodt Foundation
- National Institutes of Health [R01AG040061, R01AG047182, R01GM115911, R01AI117839, R01GM111706, R35GM130320, F31HL147482]
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ATFS-1 preferentially accumulates in dysfunctional mitochondria carrying mutated mitochondrial DNA (increment mtDNA) and facilitates mtDNA replication by promoting POLG recruitment. Inhibition of LONP-1 can improve heteroplasmy ratio and restore mitochondrial function.
The accumulation of deleterious mitochondrial DNA ( increment mtDNA) causes inherited mitochondrial diseases and ageing-associated decline in mitochondrial functions such as oxidative phosphorylation. Following mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcriptional programme to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain increment mtDNAs in heteroplasmic worms. The mechanism by which ATFS-1 promotes increment mtDNA accumulation relative to wild-type mtDNAs is unclear. Here we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria owing to degradation by the mtDNA-bound protease LONP-1, which results in the nearly exclusive association between ATFS-1 and increment mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to increment mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wild-type mtDNAs. LONP-1 inhibition in Caenorhabditis elegans and human cybrid cells improved the heteroplasmy ratio and restored oxidative phosphorylation. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1. Yang et al. report that ATFS-1 preferentially accumulates in dysfunctional mitochondria carrying mutated mitochondria DNA ( increment mtDNA) and facilitates mtDNA replication by promoting POLG recruitment, resulting in the replicative advantage of increment mtDNA and heteroplasmy maintenance.
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