Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module

Thomas D. Jackson, Jordan J. Crameri, Linden Muellner-Wong, Ann E. Frazier, Catherine S. Palmer, Luke E. Formosa, Daniella H. Hock, Kenji M. Fujihara, Tegan Stait, Alice J. Sharpe, David R. Thorburn, Michael T. Ryan, David A. Stroud, Diana Stojanovski

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8 Citations (Scopus)


Sideroflexins (SFXNs) comprise a family of five paralogous proteins (SFXN1–5) in metazoan species. SFXN1/2/3 function as mitochondrial serine transporters and are required for efficient mitochondrial one-carbon (1C) metabolism. SFXN4 is evolutionarily divergent, and mutations in SFXN4 give rise to mitochondrial disease, pointing to a distinct function of this protein in mitochondrial biology. Using a combination of genome editing, interaction studies, and quantitative proteomics, we show that loss of SFXN4 leads to an isolated complex I assembly defect and that SFXN4 interacts with the core components of the mitochondrial complex I intermediate assembly (MCIA) complex. Our findings suggest that SFXN4 is required for the incorporation of the mtDNA-encoded ND6 subunit in the ND2 assembly module of complex I. These findings provide insights into the fundamental process of complex I assembly and functional insights into a disease-causing gene belonging to the SFXN family.

Original languageEnglish
Article numbere2115566119
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
Publication statusPublished - 29 Mar 2022


  • complex assembly
  • mitochondria
  • respiratory chain
  • sideroflexins

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