ArticleHuman molecular genetics2015
An N-terminal formyl methionine on COX 1 is required for the assembly of cytochrome c oxidase.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- FAM92A Underlies Nonsyndromic Postaxial Polydactyly in Humans and an Abnormal Limb and Digit Skeletal Phenotype in Mice.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2019Trial
- N-terminal formylmethionine as a degron and a specific signal in proteostasis and stress adaptation.Experimental & molecular medicine · 2026Review
- Mechanisms of human mitochondrial leaderless mRNA translation initiation.Nature communications · 2026Article
- Translation in Mitochondrial Ribosomes.Methods in molecular biology (Clifton, N.J.) · 2023Article
- System-wide analyses reveal essential roles of N-terminal protein modification in bacterial membrane integrity.iScience · 2022Article
- Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.Nature medicine · 2021Article
- Improved lactate control with dichloroacetate in a case with severe neonatal lactic acidosis due to MTFMT mitochondrial translation disorder.Molecular genetics and metabolism reports · 2020Article
- MTFMT deficiency correlates with reduced mitochondrial integrity and enhanced host susceptibility to intracellular infection.Scientific reports · 2020Article
- One-carbon metabolism, folate, zinc and translation.Microbial biotechnology · 2020Article
- Pseudouridine and N-formylmethionine associate with left ventricular mass index: Metabolome-wide association analysis of cardiac remodeling.Journal of molecular and cellular cardiology · 2020Article
- Leigh syndrome followed by parkinsonism in an adult with homozygous c.626C>T mutation inNeurology. Genetics · 2018Article
- Mitochondrial methionylThe Journal of biological chemistry · 2018Article
- Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs.Molecular cell · 2018Article
- Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype.Neurogenetics · 2017Article
- Lack of formylated methionyl-tRNA has pleiotropic effects on Bacillus subtilis.Microbiology (Reading, England) · 2017Article
- SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.EMBO molecular medicine · 2016Article
- Regulation of translation by one-carbon metabolism in bacteria and eukaryotic organelles.The Journal of biological chemistryReview
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Authors and funding
12 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein synthesis in mitochondria is initiated by formylmethionyl-tRNA(Met) (fMet-tRNA(Met)), which requires the activity of the enzyme MTFMT to formylate the methionyl group. We investigated the molecular consequences of mutations in MTFMT in patients with Leigh syndrome or cardiomyopathy. All patients studied were compound heterozygotes. Levels of MTFMT in patient fibroblasts were almost undetectable by immunoblot analysis, and BN-PAGE analysis showed a combined oxidative phosphorylation (OXPHOS) assembly defect involving complexes I, IV and V. The synthesis of only a subset of mitochondrial polypeptides (ND5, ND4, ND1, COXII) was decreased, whereas all others were translated at normal or even increased rates. Expression of the wild-type cDNA rescued the biochemical phenotype when MTFMT was expressed near control levels, but overexpression produced a dominant-negative phenotype, completely abrogating assembly of the OXPHOS complexes, suggesting that MTFMT activity must be tightly regulated. fMet-tRNA(Met) was almost undetectable in control cells and absent in patient cells by high-resolution northern blot analysis, but accumulated in cells overexpressing MTFMT. Newly synthesized COXI was under-represented in complex IV immunoprecipitates from patient fibroblasts, and two-dimensional BN-PAGE analysis of newly synthesized mitochondrial translation products showed an accumulation of free COXI. Quantitative mass spectrophotometry of an N-terminal COXI peptide showed that the ratio of formylated to unmodified N-termini in the assembled complex IV was ∼350:1 in controls and 4:1 in patient cells. These results show that mitochondrial protein synthesis can occur with inefficient formylation of methionyl-tRNA(Met), but that assembly of complex IV is impaired if the COXI N-terminus is not formylated.
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