Mitochondrial complex I promotes kidney cancer metastasis

Divya Bezwada, Luigi Perelli, Nicholas P. Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S. Vu, Varun Sondhi, Daniel L. Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B. Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M. Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A. Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D. Courtney, Craig R. Malloy, Giannicola Genovese, Vitaly Margulis and Ralph J. DeBerardinis ()
Additional contact information
Divya Bezwada: University of Texas Southwestern Medical Center
Luigi Perelli: University of Texas MD Anderson Cancer Center
Nicholas P. Lesner: University of Texas Southwestern Medical Center
Ling Cai: University of Texas Southwestern Medical Center
Bailey Brooks: University of Texas Southwestern Medical Center
Zheng Wu: University of Texas Southwestern Medical Center
Hieu S. Vu: University of Texas Southwestern Medical Center
Varun Sondhi: University of Texas Southwestern Medical Center
Daniel L. Cassidy: University of Texas Southwestern Medical Center
Stacy Kasitinon: University of Texas Southwestern Medical Center
Sherwin Kelekar: University of Texas Southwestern Medical Center
Feng Cai: University of Texas Southwestern Medical Center
Arin B. Aurora: University of Texas Southwestern Medical Center
McKenzie Patrick: University of Texas Southwestern Medical Center
Ashley Leach: University of Texas Southwestern Medical Center
Rashed Ghandour: University of Texas Southwestern Medical Center
Yuanyuan Zhang: University of Texas Southwestern Medical Center
Duyen Do: University of Texas Southwestern Medical Center
Phyllis McDaniel: University of Texas Southwestern Medical Center
Jessica Sudderth: University of Texas Southwestern Medical Center
Dennis Dumesnil: University of Texas Southwestern Medical Center
Sara House: University of Texas Southwestern Medical Center
Tracy Rosales: University of Texas Southwestern Medical Center
Alan M. Poole: University of Texas Southwestern Medical Center
Yair Lotan: University of Texas Southwestern Medical Center
Solomon Woldu: University of Texas Southwestern Medical Center
Aditya Bagrodia: University of Texas Southwestern Medical Center
Xiaosong Meng: University of Texas Southwestern Medical Center
Jeffrey A. Cadeddu: University of Texas Southwestern Medical Center
Prashant Mishra: University of Texas Southwestern Medical Center
Javier Garcia-Bermudez: University of Texas Southwestern Medical Center
Ivan Pedrosa: University of Texas Southwestern Medical Center
Payal Kapur: University of Texas Southwestern Medical Center
Kevin D. Courtney: University of Texas Southwestern Medical Center
Craig R. Malloy: University of Texas Southwestern Medical Center
Giannicola Genovese: University of Texas MD Anderson Cancer Center
Vitaly Margulis: University of Texas Southwestern Medical Center
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center

Nature, 2024, vol. 633, issue 8031, 923-931

Abstract: Abstract Most kidney cancers are metabolically dysfunctional1–4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]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. [1,2-13C]acetate and [U-13C]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 sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings 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.

Date: 2024
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DOI: 10.1038/s41586-024-07812-3

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