title: Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage.
abstract: Decreased Indy activity extends lifespan in D. melanogaster without significant reduction in fecundity, metabolic rate, or locomotion. To understand the underlying mechanisms leading to lifespan extension in this mutant strain, we compared the genome-wide gene expression changes in the head and thorax of adult Indy mutant with control flies over the course of their lifespan. A signature enrichment analysis of metabolic and signaling pathways revealed that expression levels of genes in the oxidative phosphorylation pathway are significantly lower in Indy starting at day 20. We confirmed experimentally that complexes I and III of the electron transport chain have lower enzyme activity in Indy long-lived flies by Day 20 and predicted that reactive oxygen species (ROS) production in mitochondria could be reduced. Consistently, we found that both ROS production and protein damage are reduced in Indy with respect to control. However, we did not detect significant differences in total ATP, a phenotype that could be explained by our finding of a higher mitochondrial density in Indy mutants. Thus, one potential mechanism by which Indy mutants extend life span could be through an alteration in mitochondrial physiology leading to an increased efficiency in the ATP/ROS ratio.
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Division of Biology and Medicine, and Institute for Brain and Neural Systems, Brown University, Providence, RI 02912, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Neretti
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wang
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
authors.forename: Hieu H
authors.initials: HH
authors.lastname: Nyguyen
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.forename: Blanka
authors.initials: B
authors.lastname: Rogina
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Helfand
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism* / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology; D004331:Drosophila melanogaster; D004579:Electron Transport; D016678:Genome; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D027981:Symporters / Q000378:metabolism* / Q000502:physiology
chemical_list: D029382:Dicarboxylic Acid Transporters; D029721:Drosophila Proteins; C417606:Indy protein, Drosophila; D017382:Reactive Oxygen Species; D027981:Symporters; D000255:Adenosine Triphosphate; D010100:Oxygen