Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy
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// Fabienne C. Fiesel 1, 2 , Elle D. James 1 , Roman Hudec 1 and Wolfdieter Springer 1, 2 1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA 2 Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA Correspondence to: Fabienne C. Fiesel, email: Fiesel.Fabienne@mayo.edu Wolfdieter Springer, email: Springer.Wolfdieter@mayo.edu Keywords: PINK1; parkin; mitophagy; mitochondrial UPR; Gamitrinib Received: June 02, 2017 Accepted: October 13, 2017 Published: November 06, 2017 ABSTRACT Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset 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.
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The machine-learning classifier had excellent agreement with the established GFP-PRKN ratio algorithm and a combined Z' score of 0.79.
“There was excellent agreement between the new classifier and the established ‘GFP-PRKN ratio’ algorithm [19, 20, 25, 30] (Fig. 1C, Table S4) but the new classifier was more robust in this screening setting and had a combined Z’ score of 0.79.”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [20]
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“In addition, G-TPP significantly induced the activating transcription factors ATF3 and ATF4 as well as the ATF4/ATF5 downstream target CHOP that have been associated with mitoUPR and the interconnected mammalian integrated stress response [20, 28].”
BackgroundMitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Greene, A. W., Grenier, K., Aguileta, M. A., Muise, S., Farazifard, R., Haque, M. E., McBride, H. M., Park, D. S., & Fon, E. A. (2012) · The EMBO Reports · doi:10.1038/embor.2012.14 · Cited by 711 · cited 1× · see citing works
“Accumulation of PINK1 on the OMM can also be triggered by knockdown of the mitochondrial protease Lon [18, 39, 40] and is sufficient to induce Parkin activity and downstream mitophagy [6, 8].”
BackgroundPINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1
Pridgeon, J. W., Olzmann, J. A., Chin, L.-S., & Li, L. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050172 · Cited by 596 · see citing works
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The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations
Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W. (2010) · Autophagy · doi:10.4161/auto.6.7.13286 · Cited by 311 · cited 1× · see citing works
“A major breakthrough for the field was that the activities of both, the mitochondrial kinase PINK1 and the cytosolic E3 ubiquitin (Ub) ligase Parkin, could be linked to mitochondrial quality control (mitoQC) [3, 4] and that loss of either gene function disrupts this stress-activated and neuroprotective pathway [4, 5].”
BackgroundSelf-citationParkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation
Iguchi, M., Kujuro, Y., Okatsu, K., Koyano, F., Kosako, H., Kimura, M., Suzuki, N., Uchiyama, S., Tanaka, K., & Matsuda, N. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.467530 · Cited by 209 · see citing works
(Patho‐)physiological relevance of PINK1‐dependent ubiquitin phosphorylation
Fiesel, F. C., Ando, M., Hudec, R., Hill, A. R., Castanedes‐Casey, M., Caulfield, T. R., Moussaud‐Lamodière, E. L., Stankowski, J. N., Bauer, P. O., Lorenzo‐Betancor, O., et al. (2015) · The EMBO Reports · doi:10.15252/embr.201540514 · Cited by 185 · cited 5× · see citing works
“The following antibodies have been used for western blot (WB) or immunofluorescence (IF): beta III tubulin (#5568, CST, WB: 1/2,000 or AB9354, Millipore, IF: 1/250), FLAG (F3165, Sigma, WB: 1/150,000), GAPDH (H86504M, Meridian Life Sciences, WB: 1/500,000), LC3B (NB100-2220, Novus Biologicals, WB: 1/5,000), Miro1 (H00…”
BackgroundMethodInfluentialSelf-citationKim, J., Fiesel, F. C., Belmonte, K. C., Hudec, R., Wang, W.-X., Kim, C., Nelson, P. T., Springer, W., & Kim, J. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0121-4 · Cited by 163 · cited 2× · see citing works
“In order to quantify mitophagy rates, we used a stable HeLa clone expressing mitoKeima in addition to EGFP-Parkin and calculated the ratio of ‘acidic’ to ‘neutral’ mitoKeima fluorescence [25].”
BackgroundMethodSelf-citation
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Hou, X., Fiesel, F. C., Truban, D., Castanedes Casey, M., Lin, W.-L., Soto, A. I., Tacik, P., Rousseau, L. G., Diehl, N. N., Heckman, M. G., et al. (2018) · Autophagy · doi:10.1080/15548627.2018.1461294 · Cited by 147 · see citing works
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Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00029-w
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- Authors
- Fiesel, F. C., James, E. D., Hudec, R., & Springer, W.
- Affiliations
- Mayo Clinic (US)
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2017-11-06
- Volume
- 8
- Issue
- 63
- Pages
- 106233-106248
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5739729
- OpenAlex
- W2767205112
- Cited by
- 67
- References
- 9
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 4
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- RIKEN
- National Institute of Neurological Disorders and Stroke (R01NS085070)
- RIKEN Brain Science Institute
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- mitophagy, PINK1, Parkin, mitochondrial protein folding, mitochondrial unfolded protein response, Parkinson's disease, autophagy receptors, cancer cells, human fibroblasts, neurons, neuroprotection, neurodegeneration
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