{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSDHAF2, also known as SDH5, is a highly conserved mitochondrial assembly factor that plays an essential role in the flavinylation of the catalytic subunit SDHA, a key event required for the proper assembly and function of succinate dehydrogenase (complex II) in both the tricarboxylic acid cycle and the electron transport chain. Initial experiments in yeast established that SDHAF2 directly interacts with SDHA to promote the covalent attachment of the flavin adenine dinucleotide (FAD) cofactor, thereby enabling effective SDH‐dependent respiration. Recent structural studies have further detailed how SDHAF2, in concert with small molecule dicarboxylates, orients the flavin and capping domains of SDHA, fine‐tuning the chemical environment for FAD incorporation. In vitro reconstitution experiments in a chemically defined system have confirmed that FAD attachment to apo-SDHA is strictly dependent on SDHAF2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its biochemical function, SDHAF2 has emerged as a critical tumor suppressor gene in the context of hereditary paragangliomas and pheochromocytomas. Germline loss-of-function and imprinting of SDHAF2 have been documented in familial cases, establishing its role in neuroendocrine tumor predisposition. Mutational analyses—such as the identification of destabilizing variants that hinder its interaction with SDHA—underscore that defective SDHAF2 leads to impaired complex II assembly, accumulation of succinate, and subsequent stabilization of hypoxia-inducible factors, which in turn drive tumorigenesis. Moreover, genetic screenings and cytogenetic studies have revealed that SDHAF2-related tumors frequently show loss of the maternal allele, consistent with an imprinted mode of inheritance, while comprehensive reviews have linked such complex II assembly defects to a broad spectrum of clinical phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in mitochondrial assembly and tumor suppression, SDHAF2 has been implicated in diverse aspects of cancer progression and treatment response. In lung cancer models, loss of SDHAF2 expression has been linked to the induction of epithelial-mesenchymal transition (EMT), which is associated with increased metastasis and enhanced radiosensitivity—effects that are mediated, at least in part, by stabilization of p53. Conversely, studies in breast cancer cells indicate that SDHA flavination and complex II assembly can occur by alternative, SDHAF2-independent mechanisms, highlighting tissue-specific variability. Moreover, circulating levels of SDHAF2 mRNA have potential as predictive biomarkers for radiotherapy response, while its expression in other endocrine tissues, such as the parathyroid, appears to play a less prominent role in tumorigenesis. These combined findings reveal a multifaceted role for SDHAF2 in modulating mitochondrial function, oncogenic signaling, and clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Huai-Xiang Hao, Oleh Khalimonchuk, Margit Schraders, et al. 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