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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 \u201csilent\u201d mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1\/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1126\/sciadv.ady0240","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:59:06Z","timestamp":1756317546000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":38,"title":["Putative PINK1\/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1461-8891","authenticated-orcid":true,"given":"William M.","family":"Rosencrans","sequence":"first","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."},{"name":"National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6926-185X","authenticated-orcid":true,"given":"Ryan W.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7886-5819","authenticated-orcid":true,"given":"Logan","family":"McGraw","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2111-2415","authenticated-orcid":true,"given":"Ian","family":"Horsburgh","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."},{"name":"National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-4274","authenticated-orcid":true,"given":"Baiyi","family":"Quan","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Huynh","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4867-9230","authenticated-orcid":true,"given":"Jennifer A.","family":"Johnston","sequence":"additional","affiliation":[{"name":"NysnoBio, Mill Valley, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0191-2154","authenticated-orcid":true,"given":"David C.","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2410-2186","authenticated-orcid":true,"given":"Tsui-Fen","family":"Chou","sequence":"additional","affiliation":[{"name":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01419-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009258"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.5607\/en.2013.22.4.283"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.1002839"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47867-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.007"},{"key":"e_1_3_2_8_2","first-page":"217","article-title":"PINK1 import regulation at a crossroad of mitochondrial fate: The molecular mechanisms of PINK1 import","volume":"167","author":"Sekine S.","year":"2020","unstructured":"S. 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