title: A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila.
abstract: Diet composition is a critical determinant of lifespan, and nutrient imbalance is detrimental to health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress; transcriptional changes in metabolism, proteostasis, and immune genes; reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and mitogen-activated protein kinase (MAPK) signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, and MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging.
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Wheeler
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yolitz
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Laslo
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Alberico
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Plant Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Song
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA. Electronic address: zous@mail.nih.gov.
authors.forename: Sige
authors.initials: S
authors.lastname: Zou
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D050528:Diet, Carbohydrate-Restricted; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006727:Hormone Antagonists / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D015735:Mifepristone / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D006727:Hormone Antagonists; C117726:gig protein, Drosophila; D015735:Mifepristone; D058570:TOR Serine-Threonine Kinases; D025261:Mitochondrial Proton-Translocating ATPases; D020123:Sirolimus