Nah, Jiemin, Mahendran, Sreya, Kerouanton, Baptiste, Cui, Liang, Hock, Daniella H., Cabrera-Orefice, Alfredo, Dunlap, Kyle, Robinson, David, Tung, Desmond W.H., Leong, Sze huey, Tan, Kiat-Yi, Chothani, Sonia P., Sun, Jingjing, Dziegowska, Agnieszka, Leszczynska, Grazyna, Rackham, Owen J.L., Wittig, Ilka, Dedon, Peter, Ducker, Gregory S., Stroud, David A. and Ho, Lena (2025) Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation. Molecular Cell, 85 (14), 2759-2775.e12. (doi:10.1016/j.molcel.2025.05.033).
Abstract
Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm 5U and τm 5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
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