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Causes and Consequences of Mitochondrial Mutations

Award Number: R35GM142836
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Causes and Consequences of Mitochondrial Mutations - PROJECT SUMMARY All complex eukaryotes rely on mitochondria to generate the cellular energy needed to maintain proper organismal function. Mutations in the mitochondrial genome underly multiple diseases and have been suggested to play a general role in aging. However, understanding the causes and consequences of mitochondrial mutations is limited by a focus on mammalian models. We will characterize mitochondrial mutations and their effects on physiology in diverse eukaryotic systems, including invertebrates, plants, and micro-eukaryotes. We will address three challenges that have hindered our understanding of mitochondrial mutations. First, we will use high-fidelity sequencing to characterize rates and types of mitochondrial mutations across eukaryotes and under different environments (e.g., increased oxidative stress), resulting in a “mitochondrial mutation atlas”. Of particular interest is the frequency of C -> T transitions resulting from replication errors vs. G -> T transversions characteristic of oxidative damage. The latter are implicated in aging theories, but the former have been shown to dominate the mutational landscape in mammalian mitochondrial genomes. Second, we will quantify distinct states of oxidative phosphorylation, reactive oxygen species (ROS) production, and metabolic rate in systems with varying sources and rates of mitochondrial mutations to determine how mutations affect organelle and organismal traits. We will also explore a mechanistic link between oxidative stress and mitochondrial mutations by increasing ROS via superoxide dismutase knockdown. Third, we will examine mitonuclear protein and transcript balance in two lineages where closely related organisms have disparate lifespans: rockfishes and cave salamanders. A shift towards reduced mitochondrial protein abundances has been identified as a conserved mechanism of longevity in long-lived strains of mice and nematodes, but it is unknown if natural long-lived populations have altered mitonuclear protein balance. We will also quantify mitochondrial mutations and physiology in these species to determine how natural selection may have shaped aging through mitochondrial processes. Overall, this research will provide a complement to previous work on mammalian models, which show uniformly high mitochondrial mutation rates. It will further uncover the possibilities for mitochondrial mutations to influence cellular and organismal processes, with implications for human health, disease progression, and aging.


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: 2025 ( Subtotal = $392,149 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	5	4/4/2025	NON-COMPETING CONTINUATION	$392,149
														Subtotal = $392,149

Issue Date FY: 2024 ( Subtotal = $392,149 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	001	4	7/30/2024	NON-COMPETING CONTINUATION	$39,215
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	4	4/17/2024	NON-COMPETING CONTINUATION	$352,934
														Subtotal = $392,149

Issue Date FY: 2023 ( Subtotal = $392,149 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	3	4/11/2023	NON-COMPETING CONTINUATION	$392,149
														Subtotal = $392,149

Issue Date FY: 2022 ( Subtotal = $395,130 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	2	5/26/2022	NON-COMPETING CONTINUATION	$395,130
														Subtotal = $395,130

Issue Date FY: 2021 ( Subtotal = $395,130 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	1	6/30/2021	NEW	$395,130
														Subtotal = $395,130

Grand Total All Awards = $1,966,707

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Causes and Consequences of Mitochondrial Mutations

Award Number: R35GM142836

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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