Dynamic Coupling between Tom22 Motions and Tom40 Pore Dynamics Modulates Ion Transport in the Mitochondrial TOM Complex

TL;DR

This study shows how Tom22 movements in mitochondria affect the Tom40 pore, controlling ion transport and protein import.

Contribution

The study reveals a molecular mechanism linking Tom22 dynamics to Tom40 pore function through simulations.

Findings

Tom22 helices undergo large motions coupled to structural changes in the TOM complex.

Restraining Tom22 helices leads to a conformation of Tom40 with reduced ion permeability.

The findings align with experimental observations of reduced calcium flux in stalled TOM complexes.

Abstract

Mitochondria rely on the efficient import of proteins
to maintain
their functions and regenerate. The translocase of the outer mitochondrial
membrane (TOM) complex serves as the primary entry point for the import
of mitochondrial proteins. Previous studies have established Tom22
as a multifunctional subunit within the complex and reported mechanosensitive
gating-like behavior of the TOM complex. In this study, all-atom molecular
dynamics simulations of the TOM core complex reveal large motions
of the Tom22 helices that are coupled to global structural rearrangements
within the complex, particularly with the α2 helix within the
Tom40 pore subunit. Microseconds-long simulations with restraints
on the Tom22 helices yield an alternative conformation of the α2
helix that is associated with a reduced ion permeability. The outcome
corroborates previous experimental results that reported a reduction
in calcium ion flux for transiently stalled TOM complexes. These findings
provide a molecular view of a mechanism by which Tom22 modulates the
pore architecture of Tom40 and regulates permeability, thus linking
the receptor dynamics to the functional control of the mitochondrial
protein import.

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