{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAdenylate kinase 2 (AK2) is a multifunctional mitochondrial enzyme that not only catalyzes the interconversion of adenine nucleotides to maintain energy homeostasis but also plays essential roles in cell differentiation and organ function. For example, biallelic mutations in AK2 have been implicated in reticular dysgenesis, a severe immunodeficiency marked by an early arrest of myelopoiesis and sensorineural deafness—findings that underscore its tissue‐specific expression in the inner ear."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, during the differentiation of adipocytes and B cells, AK2 expression is markedly induced to support the unfolded protein response and proper secretory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAK2 also contributes significantly to reproductive physiology and cancer biology. In spermatozoa, distinct adenylate kinases—including AK2—localize to the mitochondrial sheath and other flagellar compartments to buffer adenine nucleotide levels, thereby ensuring proper flagellar bending, wave propagation, and ultimately motility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In parallel, AK2 can act as a negative regulator of tumor cell growth; it forms a complex with DUSP26 to enhance dephosphorylation of FADD, thereby curbing proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", whereas in other contexts its overexpression has been linked to lung adenocarcinoma progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAnimal models further highlight AK2’s indispensable role in development and signal modulation. Genetic ablation of AK2 results in early embryonic lethality and, when conditionally eliminated in the heart, it precipitates acute pump failure that gradually recovers through compensatory upregulation of other phosphotransferases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, AK2 can directly interact with and suppress the kinase activity of oncogenic BRAF in an AMP-dependent fashion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while studies in related models of Akt2 deficiency have revealed that altered nucleotide signaling contributes to myocardial hypersensitivity to β-adrenergic stimulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings elucidate the multifaceted roles of AK2 in regulating cellular energy balance, differentiation processes, and signal transduction pathways that impact development, fertility, and tumorigenesis.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chantal Lagresle-Peyrou, Emmanuelle M Six, Capucine Picard, et al. 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