Crabtree effect in kidney proximal tubule cells via late-stage glycolytic intermediates
Manjula Darshi,
Jana Tumova,
Afaf Saliba,
Jiwan Kim,
Judy Baek,
Subramaniam Pennathur,
Kumar Sharma
Affiliations
Manjula Darshi
Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jana Tumova
Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
Afaf Saliba
Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Jiwan Kim
Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Judy Baek
Department of Internal Medicine-Nephrology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
Subramaniam Pennathur
Department of Internal Medicine-Nephrology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
Kumar Sharma
Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Corresponding author
Summary: The Crabtree effect is defined as a rapid glucose-induced repression of mitochondrial oxidative metabolism and has been described in yeasts and tumor cells. Using plate-based respirometry, we identified the Crabtree effect in normal (non-tumor) kidney proximal tubule epithelial cells (PTEC) but not in other kidney cells (podocytes or mesangial cells) or mammalian cells (C2C12 myoblasts). Glucose-induced repression of respiration was prevented by reducing glycolysis at the proximal step with 2-deoxyglucose and partially reversed by pyruvate. The late-stage glycolytic intermediates glyceraldehyde 3-phosphate, 3-phosphoglycerate, and phosphoenolpyruvate, but not the early-stage glycolytic intermediates or lactate, inhibited respiration in permeabilized PTEC and kidney cortex mitochondria, mimicking the Crabtree effect. Studies in diabetic mice indicated a pattern of increased late-stage glycolytic intermediates consistent with a similar pattern occurring in vivo. Our results show the unique presence of the Crabtree effect in kidney PTEC and identify the major mediators of this effect.
