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  • One provocative possibility suggested by these findings is that the tumorigenic effects of VHL mutations in chromaffin tissue might involve dysfunction of mitochondrial complex II. Hence, we propose that in VHL-derived tumors two complementary mechanisms play a role in stabilizing HIF1α: the loss of VHL-dependent targeting of HIF1α for proteasome-mediated degradation, and a second mechanism that is dependent on low levels of HIF1α hydroxylation resulting from complex II dysfunction. The effects of HIF1α in our model were less marked than those observed with hypoxia-mimetic agents, which inhibit prolyl hydroxylases. This suggests that additional factors, besides HIF1α, might be involved in SDHB suppression. As such, it will be relevant to determine how SDHB and mitochondrial complex II are regulated in VHL type 2C variants that have been proposed to impart distinct, HIF-independent signaling outcomes [[pgen-0010008-b12],[pgen-0010008-b13]].


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