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

View ORCID ProfileSagen E. Flowers, View ORCID ProfileRushali Kothari, View ORCID ProfileYamila N. Torres Cleuren, View ORCID ProfileMelissa R. Alcorn, View ORCID ProfileChee Kiang Ewe, View ORCID ProfileGeneva Alok, View ORCID ProfilePradeep M. Joshi, View ORCID ProfileJoel H. Rothman
doi: https://doi.org/10.1101/2021.10.27.466108
Sagen E. Flowers
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Rushali Kothari
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Yamila N. Torres Cleuren
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
2Computational Biology Unit, Institute for Informatics, University of Bergen, Norway
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Melissa R. Alcorn
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Chee Kiang Ewe
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Geneva Alok
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Pradeep M. Joshi
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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Joel H. Rothman
1Department of MCD Biology and Neuroscience Research Institute, University of California Santa Barbara, CA, USA
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  • ORCID record for Joel H. Rothman
  • For correspondence: rothman@lifesci.ucsb.edu
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Abstract

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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 11, 2022.
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Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways
Sagen E. Flowers, Rushali Kothari, Yamila N. Torres Cleuren, Melissa R. Alcorn, Chee Kiang Ewe, Geneva Alok, Pradeep M. Joshi, Joel H. Rothman
bioRxiv 2021.10.27.466108; doi: https://doi.org/10.1101/2021.10.27.466108
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Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways
Sagen E. Flowers, Rushali Kothari, Yamila N. Torres Cleuren, Melissa R. Alcorn, Chee Kiang Ewe, Geneva Alok, Pradeep M. Joshi, Joel H. Rothman
bioRxiv 2021.10.27.466108; doi: https://doi.org/10.1101/2021.10.27.466108

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