Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel-Lindau syndrome

Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumors arising in the von Hippel-Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the tumor suppressor von Hippel-Lindau (pVHL). pVHL stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harboring the chuvash polycythemia VHLR200w mutation, involved in hypoxia-sensing disorders without tumor development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumors, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy resistant tumors to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumors by focusing on the mitochondria.