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Peer-reviewedCC BY-NC-NDNature Communications

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

  • Dingyi Luo1
  • Lvqin Zheng1
  • Ming Lu2
  • Ziyao Chen1
  • P Wang1
  • Qiang Guo3
  • Ning Gao4,5,6
6 affiliations
  1. 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
  2. 2State 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. [email protected]
  3. 3State 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. [email protected]
  4. 4Beijing Advanced Center of RNA Biology (BEACON), Peking University, Beijing, China. [email protected]
  5. 5National Biomedical Imaging Center, Peking University, Beijing, China. [email protected]
  6. 6State 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. [email protected]
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Abstract

Mitochondrial function critically dependents on protein quality control systems, with the m -AAA protease plays a key role at the inner mitochondrial membrane (IMM). The evolutionarily conserved prohibitins (PHBs) are essential modulators of this protease across species, yet the molecular mechanisms remain unclear. Here, we present the Cryo-EM structure of the Chaetomium thermophilum PHB ( Ct PHB) complex, revealing a cage-like assembly composed of 11 copies of PHB1/PHB2 heterodimers. Electron microscopic and biochemical analyses suggest that m -AAA proteases are enclosed within the PHB complex through interactions mediated by their SPFH-interacting motif (SIM) exposed in the intermembrane space. Further in situ cryo-ET directly visualizes these cage-protease assemblies in native mitochondria. Disruption of their interface leads to elevated m -AAA protease activity and diminished mitochondrial stress resistance. These data establish PHB complexes as spatial organizers that compartmentalize m -AAA proteases in membrane microdomains to fine tune proteolytic homeostasis. Our findings reveal the critical role of the PHB complex in maintaining mitochondrial proteostasis, providing a unified mechanistic model to explain and reconcile the pleiotropic, and often contradictive phenotypes of PHBs and m -AAA protease in mitochondrial physiology and various disease conditions.

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Cite

BibTeXRIS
BibTeX
@article{luo2026structural,
  title = {{Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease}},
  author = {Dingyi Luo and Lvqin Zheng and Ming Lu and Ziyao Chen and P Wang and Qiang Guo and Ning Gao},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-73040-0},
  url = {https://doi.org/10.1038/s41467-026-73040-0},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease
AU  - Dingyi Luo
AU  - Lvqin Zheng
AU  - Ming Lu
AU  - Ziyao Chen
AU  - P Wang
AU  - Qiang Guo
AU  - Ning Gao
PY  - 2026
DA  - 2026/05/13
JO  - Nature Communications
DO  - 10.1038/s41467-026-73040-0
UR  - https://doi.org/10.1038/s41467-026-73040-0
AB  - Mitochondrial function critically dependents on protein quality control systems, with the m -AAA protease plays a key role at the inner mitochondrial membrane (IMM). The evolutionarily conserved prohibitins (PHBs) are essential modulators of this protease across species, yet the molecular mechanisms remain unclear. Here, we present the Cryo-EM structure of the Chaetomium thermophilum PHB ( Ct PHB) complex, revealing a cage-like assembly composed of 11 copies of PHB1/PHB2 heterodimers. Electron microscopic and biochemical analyses suggest that m -AAA proteases are enclosed within the PHB complex through interactions mediated by their SPFH-interacting motif (SIM) exposed in the intermembrane space. Further in situ cryo-ET directly visualizes these cage-protease assemblies in native mitochondria. Disruption of their interface leads to elevated m -AAA protease activity and diminished mitochondrial stress resistance. These data establish PHB complexes as spatial organizers that compartmentalize m -AAA proteases in membrane microdomains to fine tune proteolytic homeostasis. Our findings reveal the critical role of the PHB complex in maintaining mitochondrial proteostasis, providing a unified mechanistic model to explain and reconcile the pleiotropic, and often contradictive phenotypes of PHBs and m -AAA protease in mitochondrial physiology and various disease conditions.
SN  - 2041-1723
ER  -