title: Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria.
abstract: TRAP1 (tumor necrosis factor receptor-associated protein 1), a mitochondrial Hsp90 family chaperone, has been identified as a critical regulator of cell survival and bioenergetics in tumor cells. To discover novel signaling networks regulated by TRAP1, we generated Drosophila TRAP1 mutants. The mutants successfully developed into adults and produced fertile progeny, showing that TRAP1 is dispensable in development and reproduction. Surprisingly, mutation or knockdown of TRAP1 markedly enhanced Drosophila survival under oxidative stress. Moreover, TRAP1 mutation ameliorated mitochondrial dysfunction and dopaminergic (DA) neuron loss induced by deletion of a familial Parkinson disease gene PINK1 (Pten-induced kinase 1) in Drosophila. Gamitrinib-triphenylphosphonium, a mitochondria-targeted Hsp90 inhibitor that increases cell death in HeLa and MCF7 cells, consistently inhibited cell death induced by oxidative stress and mitochondrial dysfunction induced by PINK1 mutation in mouse embryonic fibroblast cells and DA cell models such as SH-SY5Y and SN4741 cells. Additionally, gamitrinib-triphenylphosphonium also suppressed the defective locomotive activity and DA neuron loss in Drosophila PINK1 null mutants. In further genetic analyses, we showed enhanced expression of Thor, a downstream target gene of transcription factor FOXO, in TRAP1 mutants. Furthermore, deletion of FOXO almost nullified the protective roles of TRAP1 mutation against oxidative stress and PINK1 mutation. These results strongly suggest that inhibition of the mitochondrial chaperone TRAP1 generates a retrograde cell protective signal from mitochondria to the nucleus in a FOXO-dependent manner.
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: the National Creative Research Initiatives Center for Energy Homeostasis Regulation, School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-744, Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Yang
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Min Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: the National Creative Research Initiatives Center for Energy Homeostasis Regulation, School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-744, Korea.
authors.forename: Sekyu
authors.initials: S
authors.lastname: Choi
authors.affiliation: the National Creative Research Initiatives Center for Energy Homeostasis Regulation, School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-744, Korea.
authors.forename: Ju-Ryung
authors.initials: JR
authors.lastname: Chung
authors.affiliation: Anatomy and Cell Biology, Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan 602-714, Korea and.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Anatomy and Cell Biology, Mitochondria Hub Regulation Center, Dong-A University College of Medicine, Busan 602-714, Korea and.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: the National Creative Research Initiatives Center for Energy Homeostasis Regulation, School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-744, Korea. Electronic address: jkc@snu.ac.kr.
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
authors.affiliation: From the Departments of Pharmacology and. Electronic address: hjkoh@dau.ac.kr.
authors.forename: Hyongjong
authors.initials: H
authors.lastname: Koh
mesh_terms: D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism; D004330:Drosophila / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; D006146:Guanidines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016566:Organoselenium Compounds; D017346:Protein Serine-Threonine Kinases; C477334:FOXO protein, Drosophila; C581704:Trap1 protein, Drosophila; C557898:gamitrinib-G4; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase
keywords: Drosophila; genetics; mitochondria; neurobiology; signal transduction