Pheochromocytomas are
neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The
proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between
tumors with VHL mutations and those with disruption of the genes encoding for
succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced
oxidoreductase is detected in all three of these
tumor types, together with an angiogenesis/
hypoxia profile typical of VHL dysfunction. The
oxidoreductase defect, not previously detected in VHL-null
tumors, is explained by suppression of the SDHB
protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in
tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between
hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of
pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in
tumors.