Role of pyruvate kinase M2-mediated metabolic reprogramming during podocyte differentiation
Open Access
- 11 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (5), 1-16
- https://doi.org/10.1038/s41419-020-2481-5
Abstract
Podocytes, a type of highly specialized epithelial cells, require substantial levels of energy to maintain glomerular integrity and function, but little is known on the regulation of podocytes' energetics. Lack of metabolic analysis during podocyte development led us to explore the distribution of mitochondrial oxidative phosphorylation and glycolysis, the two major pathways of cell metabolism, in cultured podocytes during in vitro differentiation. Unexpectedly, we observed a stronger glycolytic profile, accompanied by an increased mitochondrial complexity in differentiated podocytes, indicating that mature podocytes boost both glycolysis and mitochondrial metabolism to meet their augmented energy demands. In addition, we found a shift of predominant energy source from anaerobic glycolysis in immature podocyte to oxidative phosphorylation during the differentiation process. Furthermore, we identified a crucial metabolic regulator for podocyte development, pyruvate kinase M2. Pkm2-knockdown podocytes showed dramatic reduction of energy metabolism, resulting in defects of cell differentiation. Meanwhile, podocyte-specific Pkm2-knockout (KO) mice developed worse albuminuria and podocyte injury after adriamycin treatment. We identified mammalian target of rapamycin (mTOR) as a critical regulator of PKM2 during podocyte development. Pharmacological inhibition of mTOR potently abrogated PKM2 expression and disrupted cell differentiation, indicating the existence of metabolic checkpoint that need to be satisfied in order to allow podocyte differentiation.This publication has 56 references indexed in Scilit:
- ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effectNature, 2012
- Metabolic Plasticity in Stem Cell Homeostasis and DifferentiationCell Stem Cell, 2012
- mTOR Signaling in Growth Control and DiseaseCell, 2012
- Nuclear PKM2 regulates β-catenin transactivation upon EGFR activationNature, 2011
- UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cellsThe EMBO Journal, 2011
- Bioenergetic characterization of mouse podocytesAmerican Journal of Physiology-Cell Physiology, 2010
- Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1Molecular Cell, 2010
- Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in miceAmerican Journal of Physiology-Renal Physiology, 2010
- Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA MutationsCell, 2010
- Tetracycline-Inducible Gene Expression in Conditionally Immortalized Mouse PodocytesAmerican Journal of Nephrology, 2008