Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy

Fabienne Fiesel, Elle D. James, Roman Hudec, Wolfdieter Springer

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Loss-of-function mutations in PINK1 or PARKIN are associated with earlyonset Parkinson's disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy. While this pathway is generally accepted to occur upon chemical uncoupling of mitochondria, the (patho-) physiologic relevance has been questioned. However, few studies have indicated that PINK1 and Parkin are also activated upon accumulation of misfolded proteins in the mitochondrial lumen upon overexpression of ΔOTC (Ornithine transcarbamylase). Here, we used the mitochondrial targeted HSP90 inhibitor Gamitrinib-triphenylphosphonium (G-TPP), an anti-cancer agent, to chemically interfere with mitochondrial protein folding. G-TPP treatment induced PINK1 accumulation, ubiquitin phosphorylation at Ser65, Parkin activation and its recruitment to mitochondria was specific for mitochondrial HSP90 inhibition and largely independent of mitochondrial membrane depolarization. Mitophagy induction was observed by monitoring autophagy receptor recruitment and the mitoKeima reporter. Importantly, mitophagy was not only induced in cancer cells but also in primary human fibroblasts and thereof converted neurons. G-TPP treatment might represent a novel strategy to study PINK1 and Parkin-mediated mitochondrial quality control using a more physiologically relevant stress.

Original languageEnglish (US)
Pages (from-to)106233-106248
Number of pages16
JournalOncotarget
Volume8
Issue number63
DOIs
StatePublished - Jan 1 2017

Fingerprint

Mitochondrial Degradation
Autophagy
Mitochondria
Mitochondrial Proteins
Polyubiquitin
Ornithine Carbamoyltransferase
Ubiquitin-Protein Ligases
Protein Folding
Mitochondrial Membranes
Ubiquitin
Quality Control
Organelles
Parkinson Disease
Neoplasms
Phosphotransferases
Fibroblasts
Phosphorylation
Neurons
Mutation
Proteins

Keywords

  • Gamitrinib
  • Mitochondrial UPR
  • Mitophagy
  • Parkin
  • PINK1

ASJC Scopus subject areas

  • Oncology

Cite this

Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. / Fiesel, Fabienne; James, Elle D.; Hudec, Roman; Springer, Wolfdieter.

In: Oncotarget, Vol. 8, No. 63, 01.01.2017, p. 106233-106248.

Research output: Contribution to journalArticle

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