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Causes and Consequences of Mitochondrial Mutations

线粒体突变的原因和后果

基本信息

批准号：
10629425
负责人：
Justin C Havird
金额：
$ 39.21万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

项目摘要

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.

项目总结

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lack of transcriptional coordination between mitochondrial and nuclear oxidative phosphorylation genes in the presence of two divergent mitochondrial genomes.

DOI：
10.24272/j.issn.2095-8137.2021.348
发表时间：
2022-01-18
期刊：
Zoological research
影响因子：
4.9
作者：
Xu R;Iannello M;Havird JC;Milani L;Ghiselli F
通讯作者：
Ghiselli F

Mitonuclear sex determination? Empirical evidence from bivalves.

线粒体性别决定？

DOI：
10.1101/2023.07.05.547839
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Smith,ChaseH;Mejia-Trujillo,Raquel;Breton,Sophie;Pinto,BrendanJ;Kirkpatrick,Mark;Havird,JustinC
通讯作者：
Havird,JustinC

The mtDNA mutation spectrum in the PolG mutator mouse reveals germline and somatic selection.