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 mitochondriatargeted 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, gamitrinibtriphenylphosphonium 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.

Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development

“…In addition to heightened cell proliferation (10,11) and inhibition of apoptosis (9, 12) in vivo, TRAP1 Tg mice exhibited extensive transcriptional changes, resulting in an angiogenic, pro-invasive, and cytoprotective gene signature. Widespread changes in gene expression were also observed in TRAP1 knockout mice (22) and cell type-specific responses after TRAP1 targeting (26). These data anticipate a potential role of TRAP1-directed proteostasis in mechanisms of mitochondrion-to-nucleus "retrograde" signaling (27), typically activated in response to mitochondrial dynamics (28) or organelle dysfunction (29).…”

Assessment of mitophagy in mt‐Keima Drosophila revealed an essential role of the PINK1‐Parkin pathway in mitophagy induction in vivo

“…For the ATP assay, 5 thoraces from 3-d-old flies were dissected, and the ATP concentration was measured as previously described (20). The relative ATP level was calculated by dividing the measured ATP concentration by the total protein concentration.…”

Proteomic interrogation of HSP90 and insights for medical research

“…For example, most proteomics studies so far focused on the cytosolic isoforms of HSP90; however, HSP90 inhibitors also bind the ER-located paralog, GRP94 (HSP90B1), and to a lesser extent the mitochondrial one, TRAP1 [104]. More paralog-specific inhibitors are needed to disentangle individual effects and some initial work has been done in this direction [65,105–110]. Specific interactome studies on all cellular paralogs are also needed, including some addressing explicitly the differences between HSP90α and HSP90β in the same system.…”