MTFMT (mitochondrial methionyl-tRNA formyltransferase) catalyzes the formylation of methionyl-tRNA to N-formylmethionyl-tRNA, a critical step for mitochondrial translation initiation 1. While N-formylation is not absolutely required for mitochondrial protein synthesis initiation, it is essential for efficient synthesis of mtDNA-encoded polypeptides and for proper assembly and stability of oxidative phosphorylation (OXPHOS) complexes I and IV 2. MTFMT deficiency impairs mitochondrial integrity and reduces basal NF-κB activity, increasing host susceptibility to intracellular infection 3. Pathogenic MTFMT mutations cause Combined Oxidative Phosphorylation Deficiency 15 and Mitochondrial Complex I Deficiency, Nuclear Type 27, typically presenting as Leigh syndrome or mitochondrial leukoencephalopathy 45. Clinical presentations include developmental delay, motor symptoms, basal ganglia changes, and white matter abnormalities, with symptom onset typically around 14 months 5. The c.626C>T mutation is among the most frequent disease alleles 4. Notably, patients with MTFMT mutations exhibit a milder clinical phenotype compared to Leigh syndrome caused by other nuclear defects, with 74% surviving into adulthood 5. Fibroblast analysis showing reduced complex I and IV subunits can establish causality of novel variants without requiring muscle biopsy 51.