Succinate dehydrogenase (Complex II) is unique among TCA cycle enzymes because it is embedded in the inner mitochondrial membrane. Loss-of-function mutations in SDHB (succinate dehydrogenase B subunit) are associated with:

• A Leigh syndrome due to impaired oxidative phosphorylation and energy deficit in neurons
• B Fumarase deficiency metabolic phenotype with fumarate accumulation
• C Isolated lactic acidosis with normal TCA cycle function because Complex II contributes minimally to OXPHOS
• D Paragangliomas and pheochromocytomas, through succinate-mediated inhibition of prolyl hydroxylases and HIF-1alpha stabilization ✓

Explanation

SDHB mutations (part of the SDH complex) cause succinate accumulation by impairing its oxidation to fumarate. Succinate is an oncometabolite that inhibits alpha-ketoglutarate-dependent prolyl hydroxylases (PHDs) responsible for hydroxylating and targeting HIF-1alpha for VHL-mediated proteasomal degradation. Succinate-mediated PHD inhibition stabilizes HIF-1alpha even under normoxic conditions (pseudohypoxia), driving transcription of VEGF, EPO, and metabolic genes promoting angiogenesis and tumor growth. SDH mutations cause hereditary paraganglioma-pheochromocytoma syndromes (SDHx mutations). Fumarase deficiency causes fumarate (not succinate) accumulation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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