A 29-year-old man has multifocal extra-adrenal paragangliomas. Germline sequencing shows loss-of-function mutation of one subunit of succinate dehydrogenase, and tumor tissue accumulates succinate. Which mechanism best explains the markedly increased HIF-1alpha signaling seen in these tumors?

• A Succinate directly activates the von Hippel-Lindau ubiquitin ligase, stabilizing HIF-1alpha
• B Succinate competitively inhibits prolyl hydroxylase, preventing hydroxylation of HIF-1alpha and its recognition by VHL ✓
• C Succinate allosterically activates pyruvate kinase M2, diverting glycolytic flux toward biosynthesis
• D Succinate inhibits TET methylcytosine dioxygenases, producing global DNA hypermethylation

Explanation

Prolyl hydroxylases require alpha-ketoglutarate as cosubstrate. Accumulated succinate is structurally related and competitively blocks them, so HIF-1alpha escapes hydroxylation, is not recognized by VHL for ubiquitin-mediated degradation, and accumulates even at normal oxygen tension, driving angiogenic and glycolytic genes (pseudohypoxia). Option D describes a real consequence of succinate accumulation that contributes to the hypermethylator phenotype, but it does not explain HIF-1alpha stabilization, which is what the stem asks.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.