title: Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila.
abstract: The molecular mechanisms influencing healthspan are unclear but mitochondrial function, resistance to oxidative stress and proteostasis are recurring themes. Tumor necrosis factor Receptor Associated Protein 1 (TRAP1), the mitochondrial analog of Hsp75, regulates levels of reactive oxygen species in vitro and is found expressed at higher levels in tumor cells where it is thought to play a pro-survival role. While TRAP1-directed compartmentalized protein folding is a promising target for cancer therapy, its role at the organismal level is unclear. Here we report that overexpression of TRAP1 in Drosophila extends healthspan by enhancing stress resistance, locomotor activity and fertility while depletion of TRAP1 has the opposite effect, with little effect on lifespan under both conditions. In addition, modulating TRAP1 expression promotes the nuclear translocation of homeobox protein Dve and increases expression of genes associated with the mitochondrial unfolded protein response (UPR(mt)), indicating an activation of this proteostasis pathway. Notably, independent genetic knockdown of components of the UPR(mt) pathway dampen the enhanced stress resistance observed in TRAP1 overexpression flies. Together these studies suggest that TRAP1 regulates healthspan, potentially through activation of the UPR(mt).
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA; Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824-1115, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: baqri@fas.harvard.edu.
authors.forename: Rehan M
authors.initials: RM
authors.lastname: Baqri
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA.
authors.forename: Arielle V
authors.initials: AV
authors.lastname: Pietron
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA.
authors.forename: Rewatee H
authors.initials: RH
authors.lastname: Gokhale
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA; Department of Biochemistry and Molecular Biology, 319 Biochemistry Building, Michigan State University, East Lansing, MI 48824-1319, USA.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Turner
authors.affiliation: Department of Biochemistry and Molecular Biology, 319 Biochemistry Building, Michigan State University, East Lansing, MI 48824-1319, USA; Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319, USA.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Kaguni
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Shingleton
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Kunes
authors.affiliation: Department of Zoology, Michigan State University, 203 Natural Sciences Building, East Lansing, MI 48824-1115, USA; Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824-1115, USA; Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, MI 48824-1319, USA. Electronic address: kmiller@msu.edu.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Miller
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D024101:Mitochondrial Proteins; C581704:Trap1 protein, Drosophila
keywords: Ageing; Drosophila; Healthspan; Mitochondria; TRAP1; UPR