Dynamic Coupling between Tom22 Motions and Tom40 Pore Dynamics Modulates Ion Transport in the Mitochondrial TOM
Abhishek Acharya1, Stephan Nussberger2, Shuo Wang2,3
1School of Sciences, Constructor University, Campus Ring 1, 28759 Bremen, Germany.
Journal of Chemical Information and Modeling
|October 31, 2025
Summary
Mitochondrial protein import relies on the translocase of the outer mitochondrial membrane (TOM) complex. This study reveals how Tom22 subunit movements regulate the TOM complex pore, controlling protein import and ion permeability.
Area of Science:
- Mitochondrial biology
- Molecular biophysics
- Cellular transport mechanisms
Background:
- Mitochondria require efficient protein import for function and regeneration.
- The translocase of the outer mitochondrial membrane (TOM) complex is the main entry point for mitochondrial proteins.
- Tom22 is a known multifunctional subunit of the TOM complex, with observed mechanosensitive gating-like behavior.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the TOM complex's mechanosensitive gating.
- To elucidate the role of Tom22 subunit dynamics in regulating TOM complex structure and function.
- To provide a molecular explanation for observed changes in mitochondrial calcium ion flux.
Main Methods:
- All-atom molecular dynamics simulations of the TOM core complex.
- Microseconds-long simulations utilizing restraints on Tom22 helices.
- Analysis of structural rearrangements and ion permeability changes.
Main Results:
- Large motions of Tom22 helices were observed, coupled to global structural rearrangements in the TOM complex.
- A specific interaction between Tom22 helices and the Tom40 pore subunit's α2 helix was identified.
- Simulations revealed an alternative conformation of the Tom40 α2 helix, associated with reduced ion permeability, corroborating experimental data on calcium flux.
Conclusions:
- Tom22 dynamics directly modulate the pore architecture of Tom40.
- This modulation regulates the permeability of the mitochondrial outer membrane.
- The study links Tom22 receptor dynamics to the functional control of mitochondrial protein import and ion flux.
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