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Updated: Aug 30, 2025

Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria
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Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy

Jonas Benjamin Michaelis1, Melinda Elaine Brunstein1, Süleyman Bozkurt1

  • 1Institute of Biochemistry II, Goethe University Frankfurt am Main, Faculty of Medicine, Theodor-Stern-Kai 7, Building 75, 60590, Frankfurt, Germany.

Nature Communications
|September 2, 2022
PubMed

Insights

Mitochondrial protein import defects trigger mitophagy even in healthy, polarized mitochondria. This discovery expands our understanding of mitophagy beyond membrane depolarization, crucial for disease prevention.

Area of Science:

  • Cellular Biology
  • Mitochondrial Dynamics
  • Autophagy

Background:

  • Mitophagy is vital for cellular health, removing damaged mitochondria.
  • Typically, mitophagy is triggered by mitochondrial depolarization.
  • The mechanisms inducing mitophagy without depolarization are not fully understood.

Purpose of the Study:

  • To investigate novel triggers for mitophagy.
  • To elucidate the molecular mechanisms of mitophagy induction in polarized mitochondria.
  • To identify new components involved in mitophagy regulation.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening to identify mitophagy inducers.
  • Analysis of the pre-sequence translocase-associated motor (PAM) complex.
  • Assessment of mitophagy induction in response to protein import defects and mitochondrial protein misfolding.

Main Results:

  • Loss of mitochondrial protein import by the PAM complex induces mitophagy in polarized mitochondria.
  • CRISPR/Cas9 screening identified PAM complex components as mitophagy inducers.
  • Mitochondrial protein misfolding leads to PAM complex dissociation, decreased import, and mitophagy.

Conclusions:

  • Defects in mitochondrial protein import are sufficient to induce mitophagy independently of membrane potential loss.
  • This finding broadens the known pathways for mitophagy activation.
  • The study provides a new model for mitophagy in conditions like mitochondrial protein misfolding, relevant to disease pathogenesis.

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