# Causes and Consequences of Mitochondrial Mutations

> **NIH NIH R35** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $395,130

## Abstract

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.

## Key facts

- **NIH application ID:** 10275592
- **Project number:** 1R35GM142836-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Justin C Havird
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,130
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275592

## Citation

> US National Institutes of Health, RePORTER application 10275592, Causes and Consequences of Mitochondrial Mutations (1R35GM142836-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10275592. Licensed CC0.

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