2. Academic Validation
  3. Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation

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

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: lena@ho-lab.org.
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.

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