Complex II (succinate dehydrogenase, SDH) of the electron transport chain is unique among ETC complexes because it does not pump protons across the inner mitochondrial membrane. Which subunits of SDH are tumour suppressors whose loss-of-function mutations predispose to paragangliomas and phaeochromocytomas?
- A SDHA and SDHB encode the catalytic flavoprotein and iron-sulphur subunits; SDHB mutations specifically correlate with aggressive, metastatic paragangliomas ✓
- B SDHC and SDHD encode the integral membrane anchor subunits; SDHC mutations are most closely associated with aggressive disease
- C SDHA is the primary tumour suppressor; mutations cause only gastrointestinal stromal tumours (GIST)
- D All SDH subunit mutations carry equal malignant potential in paraganglioma
Explanation
SDH is a heterotetrameric complex: SDHA (flavoprotein, FAD-linked, oxidises succinate) and SDHB (iron-sulphur clusters, transfers electrons) form the matrix-facing catalytic domain; SDHC and SDHD are membrane anchor subunits. Germline mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2 all predispose to paraganglioma-phaeochromocytoma syndrome. SDHB mutations specifically correlate with higher metastatic risk (malignant paraganglioma), whereas SDHD mutations more commonly cause head-and-neck paragangliomas. SDH loss causes succinate accumulation, which inhibits alpha-KG–dependent dioxygenases (same as 2-HG in IDH mutations), leading to epigenetic dysregulation (oncometabolite mechanism). SDHA mutations also cause GIST and Leigh syndrome.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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