Mitochondrial aminoacyl-tRNA charging and initiator Met-tRNA formylation (human); AARS2/DARS2/TARS2 + MTFMT

Translation in mitochondria uses the 22 tRNAs encoded by mitochondrial DNA, which are charged with their amino acids in the mitochondrial matrix by a separate set of nuclear-encoded aminoacyl-tRNA synthetases (the "2" synthetases, for example AARS2, DARS2 and TARS2). Each synthetase activates its amino acid with ATP and transfers it to the cognate mitochondrial tRNA. A single mitochondrial tRNA(Met) serves both initiation and elongation; the fraction destined for initiation is formylated on its methionyl group by methionyl-tRNA formyltransferase (MTFMT), using 10-formyltetrahydrofolate, to give fMet-tRNA(Met), which is recognized by the mitochondrial initiation factor and used to start synthesis of the 13 mtDNA-encoded respiratory-chain subunits. Biallelic variants in the mitochondrial synthetases cause tissue-selective disorders (for example DARS2 leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, AARS2 infantile cardiomyopathy or adult leukoencephalopathy with ovarian failure, TARS2 combined oxidative phosphorylation deficiency), and MTFMT variants cause Leigh syndrome and combined oxidative phosphorylation deficiency 15.

Concrete human module built from the four completed human reviews (AARS2, DARS2, TARS2, MTFMT); GO terms are those of their core_functions and PANTHER subfamily ids and labels are from interpro/panther/panther.obo, matching each protein's PANTHER human classification. The synthetases are listed as a variant set of one charging step because each charges a different tRNA; the set is deliberately incomplete. The other mitochondrial synthetases (for example MARS2, which charges the tRNA(Met) that MTFMT formylates, and the GatCAB-dependent Gln-tRNA route) have no gene reviews here and are named only in this note, so the charging-to-formylation connection is mediated by an unmodelled MARS2 step. Upstream mitochondrial tRNA maturation (RNase P TRMT10C-HSD17B10-PRORP, RNase Z ELAC2, CCA addition by TRNT1, and modifications) is a separate boundary: of its members only TRMT10C has a completed review, so it is not modelled. Downstream initiation (MTIF2/MTIF3) and the mitoribosome are also outside the boundary. AARS2 editing (Ser-tRNA(Ala) deacylase) activity is a fidelity function recorded in the AARS2 review and not modelled here.