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J Biol Chem. 2014 Nov 21;289(47):32729-41. doi: 10.1074/jbc.M114.610626. Epub 2014 Oct 6.

Biochemical characterization of pathogenic mutations in human mitochondrial methionyl-tRNA formyltransferase.

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From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
the Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and.
the Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114.
From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,


N-Formylation of initiator methionyl-tRNA (Met-tRNA(Met)) by methionyl-tRNA formyltransferase (MTF) is important for translation initiation in bacteria, mitochondria, and chloroplasts. Unlike all other translation systems, the metazoan mitochondrial system is unique in using a single methionine tRNA (tRNA(Met)) for both initiation and elongation. A portion of Met-tRNA(Met) is formylated for initiation, whereas the remainder is used for elongation. Recently, we showed that compound heterozygous mutations within the nuclear gene encoding human mitochondrial MTF (mt-MTF) significantly reduced mitochondrial translation efficiency, leading to combined oxidative phosphorylation deficiency and Leigh syndrome in two unrelated patients. Patient P1 has a stop codon mutation in one of the MTF genes and an S209L mutation in the other MTF gene. P2 has a S125L mutation in one of the MTF genes and the same S209L mutation as P1 in the other MTF gene. Here, we have investigated the effect of mutations at Ser-125 and Ser-209 on activities of human mt-MTF and of the corresponding mutations, Ala-89 or Ala-172, respectively, on activities of Escherichia coli MTF. The S125L mutant has 653-fold lower activity, whereas the S209L mutant has 36-fold lower activity. Thus, both patients depend upon residual activity of the S209L mutant to support low levels of mitochondrial protein synthesis. We discuss the implications of these and other results for whether the effect of the S209L mutation on mitochondrial translational efficiency is due to reduced activity of the mutant mt-MTF and/or reduced levels of the mutant mt-MTF.


Alternative Splicing; Enzyme Kinetics; Leigh Syndrome; MTFMT; Methionyl-tRNA Formyltransferase; Mitochondrial Disease; Mitochondrial Protein Synthesis; Recombinant Protein Expression; Transfer RNA (tRNA); Translation Initiation

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