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: Hyunjin Kim, Jinsung Yang, Min Ju Kim, Sekyu Choi, Ju-Ryung Chung, Jong-Min Kim, Young Hyun Yoo, Jongkyeong Chung, Hyongjong Koh
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 4 Pg. 1841-1853 (Jan 22 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 26631731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Drosophila Proteins
• FOXO protein, Drosophila
• Forkhead Transcription Factors
• Guanidines
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Organoselenium Compounds
• Trap1 protein, Drosophila
• gamitrinib-G4
• PINK1 protein, Drosophila
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Survival
• Disease Models, Animal
• Dopaminergic Neurons (cytology, metabolism)
• Drosophila (drug effects, genetics, growth & development, metabolism)
• Drosophila Proteins (antagonists & inhibitors, genetics, metabolism)
• Female
• Forkhead Transcription Factors (genetics, metabolism)
• Guanidines (pharmacology)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology)
• Male
• Mitochondria (drug effects, genetics, metabolism)
• Mutation
• Organoselenium Compounds (pharmacology)
• Oxidative Stress
• Parkinson Disease (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)