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Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway

Pin-Chao Liao1,2,3, Tzu-Ying Lin4, Catherine A Tsang5

  • 1Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. pcliao@life.nthu.edu.tw.

Communications Biology
|July 30, 2025
PubMed

Insights

The mitochondria-associated degradation pathway removes damaged mitochondrial proteins. The TOM complex facilitates this removal by acting as a bidirectional channel, crucial for mitochondrial protein quality control.

Area of Science:

  • Mitochondrial biology
  • Cellular quality control mechanisms

Background:

  • The mitochondria-associated degradation pathway (MAD) is essential for clearing damaged mitochondrial proteins via the ubiquitin-proteasome system (UPS).
  • MAD's role extends to proteins within the mitochondrial organelle, not just the outer membrane.

Purpose of the Study:

  • To reconstitute and characterize the retrotranslocation of MAD substrates from the mitochondrial matrix in a cell-free system.
  • To elucidate the role of the TOM complex in the MAD pathway.

Main Methods:

  • Cell-free reconstitution of protein retrotranslocation across mitochondrial membranes.
  • Assessing ATP dependence and membrane potential independence of retrotranslocation.
  • Investigating the effect of inhibiting the Tom40p channel on MAD substrate retrotranslocation.

Main Results:

  • Retrotranslocation of MAD substrates from the mitochondrial matrix is ATP-dependent but independent of membrane potential.
  • The TOM complex plays a role in the retrotranslocation of MAD substrates.
  • Inhibiting translocation through the Tom40p channel significantly reduces MAD substrate retrotranslocation.

Conclusions:

  • The TOM complex functions as a bidirectional channel in the mitochondrial outer membrane.
  • The TOM complex mediates the retrotranslocation of damaged mitochondrial proteins in the MAD pathway.
  • This bidirectional function of the TOM complex is critical for maintaining mitochondrial protein quality control.

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