Succinate dehydrogenase (SDH/Complex II) is the only enzyme shared between the TCA cycle and the ETC. Mutations in SDH subunits (SDHA, SDHB, SDHC, SDHD) cause hereditary paragangliomas and phaeochromocytomas via a specific molecular mechanism. What is this mechanism?
- A Loss of SDH reduces ATP production, activating mTOR-dependent proliferative signaling
- B Succinate accumulation directly activates the MAP kinase pathway through a receptor tyrosine kinase
- C SDH deficiency causes succinate accumulation which inhibits prolyl hydroxylase (PHD), preventing HIF-1alpha hydroxylation and degradation, mimicking pseudohypoxia and upregulating angiogenic/tumorigenic genes ✓
- D Reduced fumarate from SDH impairs aspartate synthesis, creating nucleotide imbalance favoring tumor growth
Explanation
SDH converts succinate → fumarate. Loss of SDH causes massive succinate accumulation. Succinate is a competitive inhibitor of alpha-ketoglutarate (2-OG)-dependent dioxygenases, including prolyl hydroxylase domain proteins (PHD1/2/3). PHDs normally hydroxylate HIF-1alpha, marking it for VHL-mediated ubiquitination and proteasomal degradation. Succinate-inhibited PHDs cannot hydroxylate HIF-1alpha → HIF-1alpha accumulates even in normoxia ('pseudohypoxia') → upregulates VEGF, erythropoietin, and other pro-tumorigenic targets. This oncometabolite concept also applies to IDH1/2 mutations (2-hydroxyglutarate inhibits TET2/PHD) and FH mutations (fumarate accumulation).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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