A primary cause of aging is thought to be reactive oxygen species (ROS) produced in mitochondria as byproducts of oxidative phosphorylation (OXPHOS). Manipulations that either increase ROS scavenging or decrease ROS production have extended longevity in some, but not all systems. Caloric or dietary restriction (CR or DR) remains the single most repeatable intervention that extends longevity in all organisms studied to date. Recent studies have identified a relationship between CR or DR, altered mitochondrial function, and extended longevity. In this proposal we present clear evidence that mtDNA haplotypes 1) can extend or shorten longevity, 2) modify the longevity-extending effects of diet restriction, 3) modify the longevity-extending effects of the insulin receptor substrate mutation chico1. These findings provide proof of principle that nuclear-mtDNA epistasis mapping is effective in uncovering genetic mechanisms of longevity extension by diet restriction. The results lead to the hypothesis that genes encoded in mtDNA are critical for the nutrient-dependent modification of longevity. We will exploit these mtDNA replacement strains to test this hypothesis using epistasis experiments with the Rpd3 - Sir2 and TOR pathways that play important roles in nutrient-based changes in longevity. These genetic constructs will also be used to test the general hypothesis that mtDNA genotype modifies longevity through changes in the level of oxidative damage. There are three specific aims that will test each of these hypotheses: 1) Does mtDNA genotype alter the Rpd3-dependent extension of longevity? We will test the hypothesis that mitochondrial genes modify the effect of Rpd3 on longevity, and Rpd3's independence from DR. 2) Does mtDNA genotype alter the Sir2-dependent effects of dietary restriction? We will test the hypothesis that mtDNA genotype modifies the role Sir2 plays in regulating the response to DR by pairing mtDNAs with over-expression and tissue specific expression constructs on different diets. 3) Does mtDNA genotype modify the TOR pathway effects on nutrient sensing and longevity extension? We will test the hypothesis that mtDNA genotype modifies the role that TOR and Tsc2 play in extending longevity by pairing mtDNAs with hypomorphic and tissue specific expression constructs of these genes.

Public Health Relevance

These experiments will provide fundamental information on how specific mitochondrial genomes interact with defined nuclear genes to determine longevity and the dietary modulation of longevity. As these interactions are evolutionarily ancient and highly conserved, the dissection of genetic pathways affecting aging in Drosophila will be very relevant to understanding this aging and age-related diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027849-05
Application #
8520128
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$291,869
Indirect Cost
$107,522
Name
Brown University
Department
Biology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Sujkowski, Alyson; Spierer, Adam N; Rajagopalan, Thiviya et al. (2018) Mito-nuclear interactions modify Drosophila exercise performance. Mitochondrion :
Rand, David M; Mossman, Jim A; Zhu, Lei et al. (2018) Mitonuclear epistasis, genotype-by-environment interactions, and personalized genomics of complex traits in Drosophila. IUBMB Life 70:1275-1288
Mossman, Jim A; Tross, Jennifer G; Jourjine, Nick A et al. (2017) Mitonuclear Interactions Mediate Transcriptional Responses to Hypoxia in Drosophila. Mol Biol Evol 34:447-466
Mossman, Jim A; Tross, Jennifer G; Li, Nan et al. (2016) Mitochondrial-Nuclear Interactions Mediate Sex-Specific Transcriptional Profiles in Drosophila. Genetics 204:613-630
Mossman, Jim A; Biancani, Leann M; Zhu, Chen-Tseh et al. (2016) Mitonuclear Epistasis for Development Time and Its Modification by Diet in Drosophila. Genetics 203:463-84
Holmbeck, Marissa A; Rand, David M (2015) Dietary Fatty Acids and Temperature Modulate Mitochondrial Function and Longevity in Drosophila. J Gerontol A Biol Sci Med Sci 70:1343-54
Holmbeck, Marissa A; Donner, Julia R; Villa-Cuesta, Eugenia et al. (2015) A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase. Dis Model Mech 8:843-54
Villa-Cuesta, Eugenia; Rand, David M (2015) Preparation of Mitochondrial Enriched Fractions for Metabolic Analysis in Drosophila. J Vis Exp :
Zhu, Chen-Tseh; Ingelmo, Paul; Rand, David M (2014) G×G×E for lifespan in Drosophila: mitochondrial, nuclear, and dietary interactions that modify longevity. PLoS Genet 10:e1004354
Villa-Cuesta, Eugenia; Holmbeck, Marissa A; Rand, David M (2014) Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila. J Cell Sci 127:2282-90

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