Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation

  • Mol Cell. 2025 Jul 17;85(14):2759-2775.e12. doi: 10.1016/j.molcel.2025.05.033.
Jiemin Nah  1 ,  Sreya Mahendran  1 ,  Baptiste Kerouanton  1 ,  Liang Cui  2 ,  Daniella H Hock  3 ,  Alfredo Cabrera-Orefice  4 ,  Kyle Dunlap  5 ,  David Robinson  6 ,  Desmond W H Tung  1 ,  Sze Huey Leong  1 ,  Kiat-Yi Tan  1 ,  Sonia P Chothani  1 ,  Jingjing Sun  2 ,  Agnieszka Dziegowska  7 ,  Grazyna Leszczynska  7 ,  Owen J L Rackham  8 ,  Ilka Wittig  4 ,  Peter Dedon  9 ,  Gregory S Ducker  5 ,  David A Stroud  3 ,  Lena Ho  10
Affiliations
  • 1. Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 2. Antimicrobial Resistance IRG, Singapore MIT Alliance for Research and Technology, Singapore, Singapore.
  • 3. Department of Biochemistry and Pharmacology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, VIC, Australia; Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • 4. Functional Proteomics Centre, Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany.
  • 5. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
  • 6. Department of Biochemistry and Pharmacology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
  • 7. Lodz University of Technology, Łódź, Poland.
  • 8. University of Southampton, Southampton, UK.
  • 9. Antimicrobial Resistance IRG, Singapore MIT Alliance for Research and Technology, Singapore, Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 10. Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore, Singapore. Electronic address: [email protected].
PMID: 40578345 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 (τm5U and τm5s²U), 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.

Keywords
complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides.
Products