{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThymidine kinase 2 (TK2) is a nuclear‐encoded enzyme that localizes to the mitochondrial matrix where it phosphorylates the pyrimidine deoxynucleosides thymidine and deoxycytidine. This phosphorylation is the first, rate‐limiting step in the mitochondrial salvage pathway for deoxyribonucleotide (dNTP) synthesis, which is essential for mtDNA replication and repair. Owing to this key role, impaired TK2 activity is closely associated with mitochondrial DNA depletion syndromes (MDS) and related myopathic as well as hepatoencephalopathic forms of the disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in TK2 have been shown to reduce its catalytic activity by altering substrate affinities, kinetic parameters, and feedback regulation. Detailed biochemical studies have demonstrated that such mutations can lead to marked decreases in Vmax or increased Km values for essential substrates (such as ATP), as well as abnormal interactions with nucleosides and nucleotide analogues. These defects compromise the synthesis of mitochondrial dTTP and dCTP pools, ultimately precipitating mtDNA depletion and the clinical manifestations observed in TK2‐related disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTK2 also plays a uniquely critical role in non‐proliferating or postmitotic cells where the de novo dNTP synthesis pathway is downregulated. In such contexts even minimal TK2 activity can be sufficient to maintain mitochondrial dTTP levels, thanks to compensatory mechanisms including cytosolic dNTP import and modulation by related enzymes. This observation explains why cells with partial TK2 deficiency can sometimes retain near‐normal dNTP pools, despite profound enzymatic defects, while still predisposing certain tissues to progressive mitochondrial dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central synthetic function, TK2 is subject to diverse regulatory and post‐translational modifications that modulate its activity under cellular stress. For example, oxidative stress can induce reversible S‐glutathionylation of TK2—specifically on cysteine residues outside the active site—thereby targeting the enzyme for degradation and further compromising mtDNA maintenance. Clinical studies have correlated the severity and progression of TK2 deficiency with factors such as age at onset, residual enzyme activity, and compensatory responses mediated by other nucleoside transporters and kinases. These findings help explain the variable phenotypic spectrum observed in patients, ranging from early‐infantile myopathy to later‐onset progressive external ophthalmoplegia and cardiomyopathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic insights into TK2 function have further been elucidated by studies identifying key amino acid residues involved in substrate binding and catalysis. These structure–function analyses have highlighted how specific mutations disrupt enzyme kinetics and regulatory feedback—findings that not only enhance our understanding of mitochondrial dNTP homeostasis but also inform the development of potential therapeutic strategies. Moreover, investigations into the dynamic regulation of TK2 expression in response to cell growth phases, radiation, and chemotherapeutic agents underscore the enzyme’s integration into a broader network responsible for both mitochondrial and nuclear genome maintenance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}, {"type": "fg_fs", "start_ref": "27", "end_ref": "30"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Mancuso, L Salviati, S Sacconi, et al. 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