The study investigates the role of mitochondrial complex I in the progression and metastasis of kidney cancer. Researchers infused 13C-labeled nutrients into over 80 patients with kidney cancer during surgical tumor resection to analyze metabolic differences between tumors and adjacent tissues. They found that clear cell renal cell carcinomas (ccRCCs) exhibit suppressed labeling of tricarboxylic acid (TCA) cycle intermediates compared to adjacent kidney tissue, indicating reduced glucose oxidation and enhanced reductive TCA cycle metabolism. However, ccRCC metastases unexpectedly show increased TCA cycle labeling compared to primary ccRCCs, suggesting a divergent metabolic program during metastasis. In mice, stimulating respiration or NADH recycling in kidney cancer cells promotes metastasis, while inhibiting electron transport chain complex I decreases metastasis. These findings indicate that metabolic properties evolve during kidney cancer progression, with mitochondrial function being limiting for metastasis but not growth at the original site. The study also highlights the importance of mitochondrial complex I in supporting metastasis, suggesting potential therapeutic targets for cancer treatment.The study investigates the role of mitochondrial complex I in the progression and metastasis of kidney cancer. Researchers infused 13C-labeled nutrients into over 80 patients with kidney cancer during surgical tumor resection to analyze metabolic differences between tumors and adjacent tissues. They found that clear cell renal cell carcinomas (ccRCCs) exhibit suppressed labeling of tricarboxylic acid (TCA) cycle intermediates compared to adjacent kidney tissue, indicating reduced glucose oxidation and enhanced reductive TCA cycle metabolism. However, ccRCC metastases unexpectedly show increased TCA cycle labeling compared to primary ccRCCs, suggesting a divergent metabolic program during metastasis. In mice, stimulating respiration or NADH recycling in kidney cancer cells promotes metastasis, while inhibiting electron transport chain complex I decreases metastasis. These findings indicate that metabolic properties evolve during kidney cancer progression, with mitochondrial function being limiting for metastasis but not growth at the original site. The study also highlights the importance of mitochondrial complex I in supporting metastasis, suggesting potential therapeutic targets for cancer treatment.