biostudies-literatureMichaelis JBDeutsche Forschungsgemeinschaft5164https://www.ebi.ac.uk/biostudies/studies/S-EPMC9440083biostudies-literatureUnknown13(1)Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfoldingNature communicationsProtein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.PMC9440083390339347259130777Bozkurt SBrunstein MEWegner MPohl CKaulich MMichaelis JBAlves LMunch CfalseProtein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy.Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding2022-01-01T00:00:00Z2022 Sep2025-04-19T10:39:06.99Z2025-04-19T10:39:06.99ZS-EPMC94400833605600110.1038/s41467-022-32564-x