The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming
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eLife Assessment
This study presents compelling evidence that the denitrosylase SCoR2 regulates cardioprotective metabolic reprogramming in the heart following ischemia/reperfusion injury. The findings are supported by a novel multi-omics approach and the integration of mouse and human data, which provides valuable insights into S-nitrosylation and cardiac metabolism. However, some conclusions remain limited by unresolved methodological issues that warrant clarification.
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Abstract
Abstract
Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2-/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways—ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism— to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target.
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eLife Assessment
This study presents compelling evidence that the denitrosylase SCoR2 regulates cardioprotective metabolic reprogramming in the heart following ischemia/reperfusion injury. The findings are supported by a novel multi-omics approach and the integration of mouse and human data, which provides valuable insights into S-nitrosylation and cardiac metabolism. However, some conclusions remain limited by unresolved methodological issues that warrant clarification.
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Reviewer #1 (Public review):
Summary:
This study shows a novel role for SCoR2 in regulating metabolic pathways in the heart to prevent injury following ischemia/reperfusion. It combines a new multi-omics method to determine SCoR2 mediated metabolic pathways in the heart. This paper would be of interest to cardiovascular researchers working on cardioprotective strategies following ischemic injury in the heart.
Strengths:
(1) Use of SCoR2KO mice subjected to I/R injury.
(2) Identification of multiple metabolic pathways in the heart by a novel multi-omics approach.
Weaknesses:
(1) Use of a global SCoR2KO mice is a limitation since the effects in the heart can be a combination of global loss of SCoR2.
(2) Lack of a cell type specific effect.
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Reviewer #2 (Public review):
Summary:
This manuscript addresses the gap in knowledge related to the cardiac function of the S-denitrosylase SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene). Genetic variants in SCoR2 have been linked to cardiovascular disease, yet their exact role in the heart remains unclear. This paper demonstrates that mice deficient in SCoR2 show significant protection in a myocardial infarction (MI) model. SCoR2 also affected ketolytic energy production, antioxidant levels, and polyol balance through the S-nitrosylation of crucial metabolic regulators.
Strengths:
(1) Addresses a well-defined gap in knowledge related to the cardiac role of SNO-CoA Reductase 2. Besides the in-depth case for this specific player, the manuscript sheds more light on the links between S-nitrosylation and metabolic reprogramming in …
Reviewer #2 (Public review):
Summary:
This manuscript addresses the gap in knowledge related to the cardiac function of the S-denitrosylase SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene). Genetic variants in SCoR2 have been linked to cardiovascular disease, yet their exact role in the heart remains unclear. This paper demonstrates that mice deficient in SCoR2 show significant protection in a myocardial infarction (MI) model. SCoR2 also affected ketolytic energy production, antioxidant levels, and polyol balance through the S-nitrosylation of crucial metabolic regulators.
Strengths:
(1) Addresses a well-defined gap in knowledge related to the cardiac role of SNO-CoA Reductase 2. Besides the in-depth case for this specific player, the manuscript sheds more light on the links between S-nitrosylation and metabolic reprogramming in the heart.
(2) Rigorous proof of requirement through the combination of gene knockout and in vivo myocardial ischemia/reperfusion.
(3) Identification of precise Cys residue for SNO-modification of BDH1 as SCoR2 target in cardiac ketolysis
Weaknesses:
(1) The experiments with BDH1 stability were performed in mutant 293 cells. Was there a difference in BDH1 stability in myocardial tissue or primary cardiomyocytes from SCoR2-null vs -WT mice? The same question extends to PKM2.
(2) In the absence of tracing experiments, the cross-sectional changes in ketolysis, glycolysis, or polyol intermediates presented in Figures 4 and 5 are suggestive at best. This needs to be stressed while describing and interpreting these results.
(3) The findings from human samples with ischemic and non-ischemic cardiomyopathy do not seem immediately or linearly in line with each other and with the model proposed from the KO mice. While the correlation holds up in the non-ischemic cardiomyopathy (increased SNO-BDH1, SNO-PKM2 with decreased SCoR2 expression), how do the authors explain the decreased SNO-BDH1 with preserved SCoR2 expression in ischemic cardiomyopathy? This seems counterintuitive as activation of ketolysis is a quite established myocardial response to ischemic stress. It may help the overall message clarity to focus the human data part on only NICM patients.
(4) This issue is partially linked to point #(3). Currently, important evidence that is lacking is the demonstration of sufficiency for SCoR2 in S-nytrosylation of targets and cardiac remodeling. Does SCoR2 overexpression in the heart or isolated cardiomyocytes reduce S-nitrosylation of BDH1 and other targets, thus affecting heart function at baseline or under stress?
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Reviewer #3 (Public review):
Summary:
This manuscript demonstrates that mice lacking the denitrosylase enzyme SCoR2/AKR1A1 demonstrate robust cardioprotection resulting from reprogramming of multiple metabolic pathways, revealing widespread, coordinated metabolic regulation by SCoR2.
Strengths:
(1) The extensive experimental evidence.
(2) The use of the knockout model.
Weaknesses:
(1) Lack of direct evidence for underlying mechanism(s).
(2) The mouse model used is not tissue-specific.
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