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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Finkelstein, David B
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Brown University
Schools of Medicine
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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
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
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
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
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
Villa-Cuesta, Eugenia; Fan, Frances; Rand, David M (2014) Rapamycin reduces Drosophila longevity under low nutrition. IOSR J Pharm 4:43-51
Meiklejohn, Colin D; Holmbeck, Marissa A; Siddiq, Mohammad A et al. (2013) An Incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila. PLoS Genet 9:e1003238
Zhu, Chen-Tseh; Rand, David M (2012) A hydrazine coupled cycling assay validates the decrease in redox ratio under starvation in Drosophila. PLoS One 7:e47584

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