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bioRxiv · 10.1101/2025.03.04.641455

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15

Kroczek, L.·Nolte, H.·Lasarzewski, Y.·Molinie, T.·Curbelo Pinero, D.·Lemke, K.·Rugarli, E.·Langer, T.
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Abstract

Mitochondria adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 reduces the import of OXPHOS-related proteins via the TIMM23-TIMM17A protein translocase, limiting OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum and induce an ATF6-related unfolded protein response. Our results demonstrate stress-dependent changes in protein import specificity as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.

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Kroczek, L., Nolte, H., Lasarzewski, Y., Molinie, T., Curbelo Pinero, D., Lemke, K., Rugarli, E., Langer, T.. 2025-03-05. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15. https://doi.org/10.1101/2025.03.04.641455

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