Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

Jonas Benjamin Michaelis, Melinda Elaine Brunstein, Süleyman Bozkurt, Ludovico Alves, Martin Wegner, Manuel Kaulich, Christian Pohl and Christian Münch ()
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Jonas Benjamin Michaelis: Goethe University Frankfurt am Main, Faculty of Medicine
Melinda Elaine Brunstein: Goethe University Frankfurt am Main, Faculty of Medicine
Süleyman Bozkurt: Goethe University Frankfurt am Main, Faculty of Medicine
Ludovico Alves: Goethe University Frankfurt am Main, Faculty of Medicine
Martin Wegner: Goethe University Frankfurt am Main, Faculty of Medicine
Manuel Kaulich: Goethe University Frankfurt am Main, Faculty of Medicine
Christian Pohl: Goethe University Frankfurt am Main, Faculty of Medicine
Christian Münch: Goethe University Frankfurt am Main, Faculty of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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 misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.

Date: 2022
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DOI: 10.1038/s41467-022-32564-x

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