Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress
Creators
-
1.
California Institute of Technology
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2.
National Institute of Neurological Disorders and Stroke
- 3. NysnoBio, Mill Valley, CA, USA.
Abstract
The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson’s disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or “silent” mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson’s disease.
Copyright and License
Copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Acknowledgement
We thank the Youle laboratory for the YFP-Parkin Mitokeima and PINK1 KO cell lines as well as various plasmids. We thank R. Youle for helpful discussions and critical review of the manuscript. We thank C. Wang for critical review. We thank Y. Chakrabarty for help with analysis of mtKeima data, ISR shRNAs, and critical review. We thank S. Sekine and L. Jae for the KI DELE1-HA 293 T line and insight into the ISR/DELE1 pathway. We thank members of the Chou and Chan laboratories for helpful discussions. We thank P. Fatheree and A. W. Garofalo for work on the development of FB231 and critical feedback, and S. Finley for compound management. We used GPT4-4o and GPT-4.5, Open AI to edit writing, code, and translate code/math into interpretable methods.
Funding
W.M.R. was supported by the NINDS Intramural program and the Center for Alzheimer’s and Related Dementia, NIA/NINDS NIH. This research was supported (in part) by the Intramural Research Program of the NIH, NINDS. This work was funded in part by the Merkin Institute for Translational Research at Caltech, NIH grant R35GM127147 (D.C.C.), and the Michael J. Fox Foundation grant US10308617B2 (J.A.J.).
Contributions
Conceptualization: W.M.R., R.W.L., I.H., and J.A.J. Methodology: W.M.R., R.W.L., L.M., T.-Y.W., and B.Q. Investigation: W.M.R., R.W.L., L.M., T.-Y.W., D.H., and B.Q. Software: W.M.R. Formal analysis: W.M.R., R.W.L., L.M., and T.-Y.W. Writing—original draft: W.M.R., R.W.L., and B.Q. Writing—review and editing: W.M.R., R.W.L., L.M., J.A.J., D.C.C., and T.-F.C. Funding acquisition: W.M.R., J.A.J., D.C.C., and T.-F.C. Supervision: W.M.R., J.A.J., D.C.C., and T.-F.C.
Data Availability
All materials can be provided by the authors pending scientific review and a completed material transfer agreement through Caltech. Requests for the material should be submitted to tfchou@caltech.edu. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Proteomics datasets have been deposited in the PRIDE database with reference code: PXD058150 (https://ebi.ac.uk/pride/archive/projects/PXD058150). All original code is available in this paper’s Supplementary Materials.
Code Availability
All original code is available in this paper’s Supplementary Materials.
Conflict of Interest
W.M.R., R.W.L., I.H., T.-Y.W., D.C.C., and T.-F.C. declare no competing interests. J.A.J. is an employee of Snohamer LLC, the parent company of Finsno Bio; serves as the CEO of NysnoBio, of which Snohamer is also the parent company; has received funding from Michael J. Fox Foundation for aspects of this work; and is an inventor on a patent describing FB231 (US10308617B2). L.M. is a current employee of Amgen Inc. All other authors declare that they have no competing interests.
Files
sciadv.ady0240.pdf
Additional details
Identifiers
- PMCID
- PMC12383277
- PMID
- 40864725
Funding
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health
- R35GM127147
Dates
- Submitted
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2025-04-10
- Accepted
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2025-07-07