Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes

J Biol Chem. 2018 Sep 28;293(39):15021-15032. doi: 10.1074/jbc.RA118.003838. Epub 2018 Aug 7.


N-Formylation of the Met-tRNAMet by the nuclearly encoded mitochondrial methionyl-tRNA formyltransferase (MTFMT) has been found to be a key determinant of protein synthesis initiation in mitochondria. In humans, mutations in the MTFMT gene result in Leigh syndrome, a progressive and severe neurometabolic disorder. However, the absolute requirement of formylation of Met-tRNAMet for protein synthesis in mammalian mitochondria is still debated. Here, we generated a Mtfmt-KO mouse fibroblast cell line and demonstrated that N-formylation of the first methionine via fMet-tRNAMet by MTFMT is not an absolute requirement for initiation of protein synthesis. However, it differentially affected the efficiency of synthesis of mtDNA-coded polypeptides. Lack of methionine N-formylation did not compromise the stability of these individual subunits but had a marked effect on the assembly and stability of the OXPHOS complexes I and IV and on their supercomplexes. In summary, N-formylation is not essential for mitochondrial protein synthesis but is critical for efficient synthesis of several mitochondrially encoded peptides and for OXPHOS complex stability and assembly into supercomplexes.

Keywords: N-formylation; gene knockout; methionine; mitochondria; mitochondrial DNA (mtDNA); mitochondrial disease; protein synthesis; transfer RNA (tRNA).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA, Mitochondrial / genetics
  • Fibroblasts / metabolism
  • Humans
  • Hydroxymethyl and Formyl Transferases / genetics*
  • Methionine / genetics*
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / genetics
  • Mutation
  • Oxidative Phosphorylation
  • Protein Biosynthesis / genetics*
  • RNA, Transfer, Amino Acyl / genetics


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • RNA, Transfer, Amino Acyl
  • tRNA(m)(Met), methionine-
  • Methionine
  • Hydroxymethyl and Formyl Transferases
  • methionyl-tRNA formyltransferase