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Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease

Dingyi Luo1, Lvqin Zheng1, Ming-Ao Lu2

  • 1State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University, Beijing, China.

Nature Communications
|May 13, 2026
PubMed

Insights

The prohibitin (PHB) complex forms a cage around the m-AAA protease, organizing mitochondrial protein quality control. This structural insight explains how PHB maintains mitochondrial health and stress resistance.

Area of Science:

  • Mitochondrial biology
  • Protein quality control
  • Structural biology

Background:

  • Mitochondrial function relies on protein quality control, particularly the m-AAA protease at the inner mitochondrial membrane.
  • Prohibitins (PHBs) are known modulators of m-AAA protease, but their interaction mechanism is unclear.

Purpose of the Study:

  • To elucidate the structural basis of the prohibitin complex's interaction with the m-AAA protease.
  • To understand the role of this complex in mitochondrial proteostasis and stress response.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) of the Chaetomium thermophilum PHB complex.
  • Biochemical analyses to study protease-PHB interactions.
  • In situ visualization in native mitochondria.

Main Results:

  • Determined the cryo-EM structure of the PHB complex, revealing an 11-heterodimer cage-like assembly.
  • Showed m-AAA proteases are enclosed within the PHB complex via SPFH-interacting motifs.
  • Demonstrated that disrupting the PHB-protease interface increases protease activity and reduces mitochondrial stress resistance.

Conclusions:

  • PHB complexes act as spatial organizers, compartmentalizing m-AAA proteases in membrane microdomains.
  • This compartmentalization fine-tunes proteolytic homeostasis, crucial for mitochondrial proteostasis.
  • Provides a mechanistic model for PHB and m-AAA protease roles in mitochondrial physiology and disease.

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