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A model for elimination of defective mitochondrial genomes

Award Number: R21AG068915
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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A model for elimination of defective mitochondrial genomes - 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 of premier importance to aging, neurodegeneration, and mitochondrial disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $194,375 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	2	7/8/2021	NON-COMPETING CONTINUATION	$194,375
														Subtotal = $194,375

Issue Date FY: 2020 ( Subtotal = $233,250 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	1	9/18/2020	NEW	$233,250
														Subtotal = $233,250

Grand Total All Awards = $427,625

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A model for elimination of defective mitochondrial genomes

Award Number: R21AG068915

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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