Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.

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

SUBMITTER: Rosencrans WM 

PROVIDER: S-EPMC12383277 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature