Structural evolution of the MTCH family of mitochondrial insertases.

Authors

Taylor A Stevens, Zhilin Luo, Camryn Lee, Masami Hazu, Erini G Galatis, Alison J Inglis, Alina Guna, Rebecca M Voorhees

Published in

Science advances. Volume 12. Issue 25. Pages eaeh2957. Jun 19, 2026. Epub Jun 17, 2026.

Abstract

We demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. MTCH insertases are conserved across holozoa and have diverged from the solute carrier 25 transporters. The cryoelectron microscopy structure of the 33-kilodalton human MTCH2 revealed that evolution of its insertase activity required loss of a transmembrane helix, which created a lipid-accessible hydrophilic groove stabilized by its unique, structured C terminus. Mutational analyses showed that MTCH insertase activity is attenuated, while experimental structures and reconstitution of hyperactive mutants demonstrated that the hydrophobicity, charge, and size of the residues that line its groove regulated MTCH function. Leveraging the MTCH2 structure, we identified the plant OM insertase and proposed a universal mechanism for OM insertion across all kingdoms of life.

PMID:
42308315
Bibliographic data and abstract were imported from PubMed on 18 Jun 2026.

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