# A model for elimination of defective mitochondrial genomes

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2020 · $233,250

## Abstract

SUMMARY
The major objective of the proposed research is to unveil mechanisms that eliminate defective mitochondrial
genomes (mtDNA) through genetic and epigenetic processes. The heteroplasmic state of mtDNA in animal cells
allows accumulation of defective mtDNAs with potential replicative advantage. Quality control systems function
to remove such deleterious mitochondrial genomes. We found that the abundance of a large deletion-bearing
mtDNA in C. elegans, uaDf5, that is normally stably maintained in a heteroplasmic state with wild-type mtDNA
(WT-mtDNA) increases with adult age and that this increased burden is passed onto offspring of older mothers.
This defective mtDNA is also elevated in mutants lacking either of two quality control systems: mitophagy (pink-
1(-)) or germline programmed cell death (PCD; ced-13(-)). Unexpectedly, however, we found that when both
pink-1 and ced-13 functions are eliminated, the opposite occurs: uaDf5 is rapidly and completely removed,
effectively curing the animal of mitochondrial disease. Even more startling, descendants of crosses between
pink-1(-) or ced-13(-) single mutant mothers with males lacking both PINK-1 and CED-13 also show rapid
removal of the deleted mtDNA, and this effect occurs irrespective of the differing descendant genotypes. These
findings lead us to hypothesize that an initiating genetic event (IGE) from these crosses triggers a potent
transgenerational epigenetic process that discriminates and effectively removes defective mtDNA. With these
foundational findings, we will investigate the mechanisms of this striking mtDNA quality control process. In Aim
1, we will analyze the effect of the IGE-triggered removal of uaDf5 on its age-dependent accumulation and
analyze its developmental timing. We will test whether the elimination process is general to other mtDNA
deletions and assess the impact of size and sequence location on the removal process. We will investigate
whether other components in the mitophagy and PCD pathways show synergy in activating removal and will test
the hypothesis that enhanced mitochondrial fission may allow for discrimination and elimination of uaDf5. In Aim
2, we will analyze the basis for the apparently epigenetic transgenerational transmission of the mtDNA quality
control process. We will evaluate the hypothesis that the dramatic amplification of WT-mtDNA that we found
occurs prior to the generations in which uaDf5 is removed is required for the removal process and that uaDf5 is
required to trigger this amplification. We will investigate whether the IGE antagonizes the mitochondrial UPR,
which protects uaDf5 from removal. We will test the hypothesis that the IGE is triggered specifically by paternal
loss of PINK-1 and CED-13. Finally, we will assess whether the IGE-activated epigenetic process is transmitted
through the nucleus or cytoplasm/mitochondria. These studies will contribute to our understanding of how a
healthy mitochondrial genome is maintained, a problem o...

## Key facts

- **NIH application ID:** 10043796
- **Project number:** 1R21AG068915-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Joel H. Rothman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043796

## Citation

> US National Institutes of Health, RePORTER application 10043796, A model for elimination of defective mitochondrial genomes (1R21AG068915-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043796. Licensed CC0.

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