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 tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel–Lindau tumour-suppressor protein, which 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 harbouring the Chuvash polycythaemia VHL^R200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, 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 tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.

线粒体是细胞内氧气的主要消费者。线粒体如何感知氧气水平仍然未知。在这里，我们展示了 TFAM 的氧敏感调节，这是一种线粒体转录和复制的激活剂，其改变与 von Hippel-Lindau 综合征中出现的肿瘤有关。TFAM 被 EGLN3 羟基化，随后被 von Hippel-Lindau 肿瘤抑制蛋白结合，该蛋白通过阻止线粒体蛋白水解来稳定 TFAM。缺乏野生型VHL或 EGLN3 失活的细胞线粒体质量减少。导致不同临床表现的致瘤性 VHL 变体无法结合羟基化TFAM 。相反，含有楚瓦什红细胞增多症VHL ^{R200W的细胞}突变，涉及缺氧感应障碍而没有肿瘤发展，能够结合羟基化 TFAM。因此，VHL 相关肿瘤，如嗜铬细胞瘤和肾细胞癌细胞，显示出低线粒体含量，这表明受损的线粒体生物发生与 VHL 肿瘤发生有关。最后，通过靶向 LONP1 来抑制蛋白水解会增加 VHL 缺陷细胞中的线粒体含量，并使耐药肿瘤对索拉非尼治疗敏感。我们的研究结果提供了药理学途径，通过关注线粒体来使耐药 VHL 肿瘤敏感。