Mitochondrial complex I promotes kidney cancer metastasis
成果类型：
Article
署名作者：
[Anonymous]
刊物名称：
Nature
ISSN/ISSBN：
0028-4483
DOI：
10.1038/s41586-024-07812-3
发表日期：
2024-09-26
页码：
923-931
关键词：
摘要：
Most kidney cancers are metabolically dysfunctional(1-4), but how this dysfunction afects cancer progression in humans is unknown. We infused C-13-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-C-13]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-C-13]acetate and [U-C-13]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufcient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These fndings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.