TK2 (thymidine kinase 2) is a mitochondrial matrix protein that phosphorylates pyrimidine deoxynucleosides—thymidine, deoxycytidine, and deoxyuridine—to their corresponding monophosphates 1. This activity is essential for the salvage pathway that supplies pyrimidine nucleotides for mitochondrial DNA (mtDNA) synthesis and maintenance, particularly in non-replicating cells where cytosolic dNTP synthesis is downregulated 2. TK2 functions alongside DGUOK to sustain mtDNA replication in these metabolic contexts 2. Autosomal recessive TK2 mutations cause mitochondrial DNA depletion syndrome 2 and progressive external ophthalmoplegia with mtDNA deletions, characterized by severe mtDNA depletion or multiple mtDNA deletions 3. Three distinct clinical phenotypes emerge: infantile-onset (42.4% of cases) with severe mtDNA depletion and median survival of 1 year, childhood-onset (40.2%) with moderate progression and median survival of ≥13 years, and late-onset (17.4%) with slow progression and median survival of 23 years 3. All presentations manifest primarily as myopathy with variable neurological involvement 3. Recent compassionate use studies demonstrate clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies in TK2-deficient patients, with improvements in motor function and stabilization of disease progression 4. These emerging interventions represent a significant advancement, as no efficacious therapy previously existed for this severe disorder 5.