PT  - JOURNAL ARTICLE
AU  - Sagen E. Flowers
AU  - Rushali Kothari
AU  - Yamila N. Torres Cleuren
AU  - Melissa R. Alcorn
AU  - Chee Kiang Ewe
AU  - Geneva Alok
AU  - Pradeep M. Joshi
AU  - Joel H. Rothman
TI  - Regulation of defective mitochondrial DNA accumulation and transmission in <em>C. elegans</em> by the programmed cell death and aging pathways
AID  - 10.1101/2021.10.27.466108
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.10.27.466108
4099  - http://biorxiv.org/content/early/2022/05/11/2021.10.27.466108.short
4100  - http://biorxiv.org/content/early/2022/05/11/2021.10.27.466108.full
AB  - 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 C. elegans to attenuate germline abundance of a 3.1 kb mtDNA deletion mutation, uaDf5, 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 mtDNAuaDf5 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 mtDNAuaDf5 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 uaDf5 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.Competing Interest StatementThe authors have declared no competing interest.