Mitochondria were once simply considered organelles that generate ATP but are now known to impact aging and age-related diseases through their myriad effects on nuclear transcription and translation. Maternal transmission of pathogenic mitochondrial DNA (mtDNA) could be prevented by mitochondrial replacement therapy. This cure, however, risks inducing mitonuclear conflicts, whose effects may not become apparent until late in life and may differ between the sexes. The proposed project will develop the crustacean Tigriopus californicus as a new model for the effect of mitochondria and mitonuclear interactions on sex-specific aging, including assays of mortality rate, mtDNA content, oxidative stress and gene expression. The species is particularly suited for experimental work in that is easily raised in the laboratory, has a short life cycle, is amenable to multiple generations of controlled crosses and has abundant genomic resources (including full genomes and transcriptomes for multiple populations). Further, it is an emerging model for understanding mitonuclear interactions, in part because viable and fertile hybrids are easily produced in crosses between populations with tremendously divergent mtDNA. The system also has the advantage that sex-specific mitochondrial effects will not be confounded by the presence of sex chromosomes, because the species does not have sex chromosomes (instead, sex determination is polygenic). This study will focus on reciprocal F1 crosses between two populations at ~19% mtDNA divergence, with substantial differences across all 37 loci, including non-synonymous changes for all 13 protein coding loci. Replicated parental and reciprocal F1 lines will be assayed for sex-specific mortality rate, lifespan, mitochondrial DNA content and deletion ratio, oxidative stress (ELISA quantification of 8-OH- dG) and gene expression (RNAseq). Weighted gene co-expression analysis (WGCNA) will be used to identify nuclear gene modules that share co-expression networks with mitochondrially- encoded genes, and to relate modules to aging phenotypes. Development of this new model system will broaden our understanding of the mitochondrial basis of aging, and will provide an unprecedented opportunity to assess effects of mutations throughout the mitochondrial genome.

Public Health Relevance

Mitochondrial function is known to influence normal senescence as well as a range of age- related diseases such as cancer, intestinal barrier dysfunction, chronic obstructive pulmonary disease (COPD) and diabetes. Mismatch between mitochondrial and nuclear genes can decrease mitochondrial function, and this is a particular problem for mitochondrial replacement therapy. This project develops Tigriopus californicus as a new invertebrate model to test how mutations throughout the mitochondrial genome affect mortality, mtDNA content and deletion, oxidative stress and gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG055873-02
Application #
9440316
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Macchiarini, Francesca
Project Start
2017-03-01
Project End
2019-02-28
Budget Start
2018-03-15
Budget End
2019-02-28
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033