AK2 (adenylate kinase 2) is a mitochondrial intermembrane space protein that catalyzes reversible phosphate transfer between ATP and AMP, maintaining adenine nucleotide homeostasis critical for cellular energy metabolism 1. As a key regulator of oxidative phosphorylation (OXPHOS), AK2 localizes near ATP synthase where it regenerates ADP as substrate for ATP synthesis in an NADH-dependent manner, acting as a metabolic gatekeeper that links ATP production to the cell's energy state 2. AK2 is essential for hematopoietic differentiation; its deficiency causes reticular dysgenesis, a severe combined immunodeficiency characterized by profound neutropenia and lymphopenia, due to blocked lymphoid and myeloid cell differentiation 13. Beyond energy metabolism, AK2 functions as an AMP sensor that suppresses BRAF activity during energy stress, indicating a role in metabolic regulation of cell proliferation 4. AK2 mutations are associated with congenital neutropenia syndromes 5, and AK2 dysregulation contributes to various malignancies including hepatocellular carcinoma, lung adenocarcinoma, and breast cancer 4. Additionally, AK2 interacts with α-synuclein to modulate mitochondrial ATP homeostasis in a conformation-dependent manner, with potential relevance to Parkinson's disease pathophysiology 6. Therapeutically, ZDHHC21-mediated palmitoylation of AK2 enhances OXPHOS in acute myeloid leukemia stem cells; ZDHHC21 inhibition suppresses AML growth and enhances chemotherapy efficacy 7.