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

doi:10.1016/j.isci.2023.106462

Crabtree effect in kidney proximal tubule cells via late-stage glycolytic intermediates

iScience. 2023 Mar 21;26(4):106462. doi: 10.1016/j.isci.2023.106462. eCollection 2023 Apr 21.

Authors

Manjula Darshi¹, Jana Tumova^{1

2}, Afaf Saliba¹, Jiwan Kim^{1

3}, Judy Baek⁴, Subramaniam Pennathur⁴, Kumar Sharma¹

Affiliations

¹ Division of Nephrology, Department of Medicine, Center for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
² Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
³ Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Department of Internal Medicine-Nephrology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

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.

Keywords: Biochemistry; Cell biology; Physiology.

Abstract

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