{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSDHA encodes the flavoprotein subunit of mitochondrial complex II, a key enzyme interconnecting the tricarboxylic acid cycle with the electron transport chain. By catalyzing succinate’s oxidation to fumarate, SDHA not only drives cellular energy production but also contributes to several regulatory mechanisms. Post‐translational modifications—including flavinylation and desuccinylation—further fine‐tune SDHA’s enzymatic activity, and evolutionary selection appears to have maintained distinct SDHA alleles to balance its critical roles in oxidative metabolism. These fundamental biochemical aspects have been illuminated by investigations into complex‐II assembly and its regulation in both normal physiology and in settings of metabolic stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations affecting SDHA have emerged as pivotal events in the pathogenesis of several tumors. In gastrointestinal stromal tumors (GISTs) and related neoplasms, loss of SDHA expression—often alongside destabilization of the entire SDH complex—leads to succinate accumulation, which in turn disrupts α‐ketoglutarate–dependent dioxygenases and epigenetic regulation. Germline and somatic SDHA alterations have been implicated in a spectrum of cancers including KIT/PDGFRA–wild‐type GISTs, paragangliomas, pheochromocytomas, and even renal cell carcinomas. Diagnostic immunohistochemistry targeting SDHA (often in combination with SDHB assessment) has proven valuable to triage patients for further genetic work‐up, with studies delineating distinct molecular and clinical phenotypes linked to SDHA inactivation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond tumorigenesis, aberrant SDHA function is implicated in diverse non‐neoplastic conditions. Altered complex II activity due to SDHA mutations contributes to mitochondrial dysfunction manifesting in cardiomyopathies—including rare dominantly inherited neonatal dilated cardiomyopathy and the cardiac pathology observed in Barth syndrome—as well as in optic neuropathies and inflammatory disorders such as ulcerative colitis. Moreover, modulation of SDHA levels has been shown to influence metabolic reprogramming during the induction of pluripotency, underscoring its broader role in cellular energy remodeling and stress responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Charis Eng, Maija Kiuru, Magali J Fernandez, et al. 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