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

Author

Listed:
  • 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
    Buchmann Institute for Molecular Life Sciences)

  • Martin Wegner

    (Goethe University Frankfurt am Main, Faculty of Medicine)

  • Manuel Kaulich

    (Goethe University Frankfurt am Main, Faculty of Medicine
    Frankfurt Cancer Institute
    Cardio-Pulmonary Institute)

  • Christian Pohl

    (Goethe University Frankfurt am Main, Faculty of Medicine
    Buchmann Institute for Molecular Life Sciences
    Discovery Neuroscience, AbbVie Deutschland GmbH & Co KG)

  • Christian Münch

    (Goethe University Frankfurt am Main, Faculty of Medicine
    Frankfurt Cancer Institute
    Cardio-Pulmonary Institute)

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.

Suggested Citation

  • Jonas Benjamin Michaelis & Melinda Elaine Brunstein & Süleyman Bozkurt & Ludovico Alves & Martin Wegner & Manuel Kaulich & Christian Pohl & Christian Münch, 2022. "Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32564-x
    DOI: 10.1038/s41467-022-32564-x
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    References listed on IDEAS

    as
    1. Christian Münch & J. Wade Harper, 2016. "Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation," Nature, Nature, vol. 534(7609), pages 710-713, June.
    2. Chun-Shik Shin & Shuxia Meng & Spiros D. Garbis & Annie Moradian & Robert W. Taylor & Michael J. Sweredoski & Brett Lomenick & David C. Chan, 2021. "LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Atsushi Hoshino & Wei-jia Wang & Shogo Wada & Chris McDermott-Roe & Chantell S. Evans & Bridget Gosis & Michael P. Morley & Komal S. Rathi & Jian Li & Kristina Li & Steven Yang & Meagan J. McManus & C, 2019. "The ADP/ATP translocase drives mitophagy independent of nucleotide exchange," Nature, Nature, vol. 575(7782), pages 375-379, November.
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