Regulation of defective mitochondrial DNA accumulation and transmission in by the programmed cell death and aging pathways.

TitleRegulation of defective mitochondrial DNA accumulation and transmission in by the programmed cell death and aging pathways.
Publication TypeJournal Article
Year of Publication2023
AuthorsFlowers S, Kothari R, Cleuren YNTorres, Alcorn MR, Ewe CKiang, Alok G, Fiallo SL, Joshi PM, Rothman JH
Date Published2023 Oct 02
KeywordsAging, Animals, Apoptosis, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Caspases, DNA, Mitochondrial

The heteroplasmic state of eukaryotic cells allows for cryptic accumulation of defective mitochondrial genomes (mtDNA). 'Purifying selection' mechanisms operate to remove such dysfunctional mtDNAs. We found that activators of programmed cell death (PCD), including the CED-3 and CSP-1 caspases, the BH3-only protein CED-13, and PCD corpse engulfment factors, are required in to attenuate germline abundance of a 3.1-kb mtDNA deletion mutation, , which is normally stably maintained in heteroplasmy with wildtype mtDNA. In contrast, removal of CED-4/Apaf1 or a mutation in the CED-4-interacting prodomain of CED-3, do not increase accumulation of the defective mtDNA, suggesting induction of a non-canonical germline PCD mechanism or non-apoptotic action of the CED-13/caspase axis. We also found that the abundance of germline mtDNA reproducibly increases with age of the mothers. This effect is transmitted to the offspring of mothers, with only partial intergenerational removal of the defective mtDNA. In mutants with elevated mtDNA levels, this removal is enhanced in older mothers, suggesting an age-dependent mechanism of mtDNA quality control. Indeed, we found that both steady-state and age-dependent accumulation rates of are markedly decreased in long-lived, and increased in short-lived, mutants. These findings reveal that regulators of both PCD and the aging program are required for germline mtDNA quality control and its intergenerational transmission.

Alternate JournalElife
PubMed ID37782016
PubMed Central IDPMC10545429
Grant ListR01 HD081266 / HD / NICHD NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States
R01 GM143771 / GM / NIGMS NIH HHS / United States
R01 HD082347 / HD / NICHD NIH HHS / United States
R21 AG068915 / AG / NIA NIH HHS / United States