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

机译：S-亚硝基-CoA还原酶系统进行的代谢重编程可防止肾脏损伤

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摘要

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-nitrosoCoA (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 aldoketo 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.
机译：内皮型一氧化氮合酶（eNOS）具有抗肾脏损伤的保护作用，但对该保护作用的分子机制了解甚少（1,2）。基于一氧化氮的细胞信号传导通常由蛋白质S-亚硝基化介导，Sys残基的氧化修饰形成S-亚硝基硫醇（SNO）。 S-亚硝基化作用可调节所有功能类别的蛋白质，并受包括S-亚硝化酶和脱亚硝化酶的酶促机制控制，分别从蛋白质中添加和去除SNO（3,4）。在酿酒酵母中，经典的代谢中间辅酶A（CoA）通过与一氧化氮结合形成S-nitrosoCoA（SNO-CoA）而成为SNOs的内源性来源，而SNO-CoA则是蛋白质的S-亚硝基化反应。由其同源的脱亚硝化酶SNO-CoA还原酶（SCoR）（5）控制。哺乳动物具有酵母SCoR的功能同源物，该酶是醛酮还原酶家族成员（AKR1A1）（5），具有未知的生理作用。在这里，我们报告SNO-CoA-AKR1A1系统在肾小管中高度表达，在此系统在重新编程中间代谢中转导eNOS的活性，从而保护肾脏免受急性肾脏损伤。具体而言，在小鼠中删除Akr1a1以降低SCoR活性可增加蛋白S-亚硝基化，防止急性肾损伤并改善生存，而当Enos（也称为Nos3）也被删除时，这种保护就会丢失。代谢谱分析与基于质谱的无偏质谱鉴定表明，SNO-CoA-SCoR系统的保护作用是通过新的调控位点抑制丙酮酸激酶M2（PKM2）的S-亚硝基化，从而平衡燃料利用率（ （通过糖酵解）和氧化还原保护（通过戊糖磷酸分流器）。从小鼠近端肾小管有针对性的PKM2删除准确地概括了Akr1a1（-/-）小鼠中S-亚硝基化的保护和机制作用，而对S-亚硝基化难治的Cys突变PKM2则否定了SNO-CoA生物活性。我们的研究结果确定了SNO-CoA-SCoR系统在哺乳动物中的生理功能，描述了肾脏新陈代谢和分化组织中PKM2的新调控，并为肾脏损伤提供了新的治疗意义。

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  • 来源
    《Nature》 |2019年第7737期|96-100|共5页
  • 作者

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

  • 作者单位

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA;

    Case Western Reserve Univ, Sch Med, Ctr Prote & Bioinformat, Cleveland, OH USA;

    Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA|Harvard Med Sch, Boston, MA USA|Broad Inst MIT & Harvard, Cambridge, MA USA;

    Harvard Med Sch, Boston, MA USA|Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA|Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA;

    Harvard Med Sch, Boston, MA USA|Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA|Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA|Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA;

    Case Western Reserve Univ, Dept Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Cleveland, OH 44106 USA|Univ Hosp Cleveland, Med Ctr, Harrington Discovery Inst, Cleveland, OH 44106 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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