Succinate dehydrogenase (SDH, Complex II) is unique among the TCA cycle enzymes because it is also an integral component of the electron transport chain. Mutations in SDHB, SDHC, or SDHD subunit genes predispose to paragangliomas and pheochromocytomas. The carcinogenic mechanism involves accumulation of which metabolite?
- A Succinate, which inhibits alpha-ketoglutarate-dependent dioxygenases including HIF-PHD, leading to pseudohypoxia ✓
- B Fumarate, which inhibits HIF prolyl hydroxylases
- C Malate, which activates oncogenic signaling pathways
- D Citrate, which is exported for fatty acid synthesis supporting tumor growth
Explanation
SDH mutations cause accumulation of succinate, which acts as a competitive inhibitor of alpha-ketoglutarate (2-oxoglutarate)-dependent dioxygenases — including HIF-1alpha prolyl hydroxylase (PHD), which normally marks HIF-1alpha for proteasomal degradation. Succinate accumulation therefore stabilizes HIF-1alpha (pseudohypoxia), activating hypoxia-response genes including VEGF and erythropoietin, promoting neovascularization and tumor growth. Succinate also inhibits TET methylcytosine dioxygenases and histone demethylases (KDMs), causing epigenetic silencing of tumor suppressor genes — the 'succinate-oncometabolite hypothesis'.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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