bims-mitpro 2025-11-02 papers

Issue of 2025–11–02
two papers selected by
Andreas Kohler, Umeå University

J Chem Inf Model. 2025 Oct 31.

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

Abhishek Acharya, Stephan Nussberger, Shuo Wang, Ulrich Kleinekathöfer.

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.

DOI: https://doi.org/10.1021/acs.jcim.5c01761

Nat Cell Biol. 2025 Oct 31.

Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.

Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.

The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.

DOI: https://doi.org/10.1038/s41556-025-01799-3