Journal Article

Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury

Zhang, Rongli, Stomberski, Colin T., Hausladen, Alfred, Zhou, Hua-Lin, Stamler, Jonathan S., Rhee, Eugene P., Anand, Puneet, Wang, Liwen, Karumanchi, S. Ananth, Parikh, Samir M., Qian, Zhaoxia

2019

Overview

Endothelial nitric oxide synthase (eNOS) is protective against kidney injury, but the molecular mechanisms of this protection are poorly understood 1 , 2 . Nitric oxide-based cellular signalling is generally mediated by protein S -nitrosylation, the oxidative modification of Cys residues to form S -nitrosothiols (SNOs). S -nitrosylation regulates proteins in all functional classes, and is controlled by enzymatic machinery that includes S -nitrosylases and denitrosylases, which add and remove SNO from proteins, respectively 3 , 4 . In Saccharomyces cerevisiae , the classic metabolic intermediate co-enzyme A (CoA) serves as an endogenous source of SNOs through its conjugation with nitric oxide to form S -nitroso-CoA (SNO-CoA), and S -nitrosylation of proteins by SNO-CoA is governed by its cognate denitrosylase, SNO-CoA reductase (SCoR) 5 . Mammals possess a functional homologue of yeast SCoR, an aldo-keto reductase family member (AKR1A1) 5 with an unknown physiological role. Here we report that the SNO-CoA–AKR1A1 system is highly expressed in renal proximal tubules, where it transduces the activity of eNOS in reprogramming intermediary metabolism, thereby protecting kidneys against acute kidney injury. Specifically, deletion of Akr1a1 in mice to reduce SCoR activity increased protein S -nitrosylation, protected against acute kidney injury and improved survival, whereas this protection was lost when Enos (also known as Nos3 ) was also deleted. Metabolic profiling coupled with unbiased mass spectrometry-based SNO-protein identification revealed that protection by the SNO-CoA–SCoR system is mediated by inhibitory S -nitrosylation of pyruvate kinase M2 (PKM2) through a novel locus of regulation, thereby balancing fuel utilization (through glycolysis) with redox protection (through the pentose phosphate shunt). Targeted deletion of PKM2 from mouse proximal tubules recapitulated precisely the protective and mechanistic effects of S -nitrosylation in Akr1a1 −/− mice, whereas Cys-mutant PKM2, which is refractory to S -nitrosylation, negated SNO-CoA bioactivity. Our results identify a physiological function of the SNO-CoA–SCoR system in mammals, describe new regulation of renal metabolism and of PKM2 in differentiated tissues, and offer a novel perspective on kidney injury with therapeutic implications. AKR1A1-regulated protein S- nitrosylation protects against kidney injury through PKM2-mediated metabolic reprogramming.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/51 / 631/337/458/2386 / 631/443/319/320 / 64/60 / 692/699/1585/4 / 82 / 82/29 / 82/58 / 82/80 / 82/83 / Acute kidney failure / Acute Kidney Injury - enzymology / Acute Kidney Injury - prevention & control / Aldehyde Reductase - deficiency / Aldehyde Reductase - genetics / Aldehyde Reductase - metabolism / Animals / Baking yeast / Biological activity / Cardiovascular disease / Care and treatment / Cell Line / Clonal deletion / Coenzyme A - metabolism / Conjugation / Criminal investigation / Endothelium / Enzymes / Female / Gene deletion / Glucose metabolism / Glycolysis / HEK293 Cells / Homology / Humanities and Social Sciences / Humans / Injury prevention / Kidney research / Kidney Tubules, Proximal - enzymology / Kidneys / Kinases / Letter / Machinery / Male / Mammals / Mass spectrometry / Mass spectroscopy / Medical schools / Metabolic Engineering / Metabolism / Mice / Molecular modelling / Monosaccharides / multidisciplinary / Mutation / Nitric oxide / Nitric Oxide Synthase Type III - metabolism / Nitric-oxide synthase / Nitrogen oxides / Nitrosoamines / Oxidation-Reduction / Oxidoreductases - metabolism / Pentose / Pentose Phosphate Pathway / Phosphates / Physiological aspects / Physiology / Protein Multimerization / Protein S / Proteins / Proximal tubules / Pyruvate kinase / Pyruvate Kinase - antagonists & inhibitors / Pyruvate Kinase - deficiency / Pyruvate Kinase - genetics / Pyruvate Kinase - metabolism / Pyruvic acid / Reductase / Resveratrol / Saccharomyces cerevisiae / Science / Science (multidisciplinary) / Scientific imaging / Spectroscopy / Yeast