ArticleRedox biology2024
Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation.
Article in Redox biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- Altered Acylcarnitine Metabolism in cardiac diseases: From molecular mechanisms to translational potential.International journal of cardiology. Heart & vasculature · 2026Review
- SIRT5-Mediated Desuccinylation of ACAA2 Protects Against Calcium Oxalate-Induced Kidney Injury by Regulating Fatty Acid Oxidation to Suppress Mitochondrial Oxidative Injury and Ferroptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The Trajectory of Epigenetic Chromatin Remodeling in Cardiometabolic Disease and its Therapeutic Implications.Journal of cardiovascular translational research · 2026Review
- Magnesium and Diabetes: A Review of Recent Studies on the Efficacy of Supplementation with Mg in Humans Suffering from This Chronic Metabolic Disease.International journal of molecular sciences · 2026Review
- Article
- SIRT5-mediated HSDL2 desuccinylation promotes diabetic-associated cognitive dysfunction via disrupting mitochondrial TRAP1.Cell biology and toxicology · 2026Article
- Beyond deacetylation: crosstalk mechanisms and context-dependent regulation of sirtuin non-classical enzymatic functions in disease.Molecular medicine (Cambridge, Mass.) · 2026Review
- Cardiac metabolic remodeling drives dicarbonyl stress-induced mitochondrial dysfunction in experimental heart failure with preserved ejection fraction.American journal of physiology. Heart and circulatory physiology · 2026Article
- Succinylation modification in diabetes and diabetic complications: Mechanisms and functions (Review).Molecular medicine reports · 2026Review
- Organelle homeostasis disruption: A driving force in the progression of cardiomyopathy (Review).Experimental and therapeutic medicine · 2026Review
- Unveiling the importance of SIRT5 for cardiac health and disease in an era of increasing longevity.GeroScience · 2026Review
- Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review).International journal of molecular medicine · 2026Review
- The role and therapeutic potential of succinate and succinylation in cardiovascular diseases.Clinical epigenetics · 2026Review
- NPM3 functions as a lactyltransferase to promote necroptosis in male diabetic cardiomyopathy mice models via FASN transcription modulation.Nature communications · 2026Article
- Integrative insights into fatty acid metabolism in diabetic cardiomyopathy: From molecular mechanisms to therapeutic strategies.iScience · 2026Review
- Diabetes and its complications: molecular mechanisms, prevention and treatment.Signal transduction and targeted therapy · 2026Review
- Suboptimal lipid management is associated with subclinical left ventricular dysfunction in type 2 diabetes mellitus patients with preserved ejection fraction: a cardiac magnetic resonance feature-tracking study.BMC cardiovascular disorders · 2026Article
- Integrated Bulk and Single-Cell Transcriptomics Reveals Cell-Type-Specific Fatty Acid Metabolic Dysregulation and Candidate Biomarkers in Diabetic Foot Ulcers.Clinical, cosmetic and investigational dermatology · 2026Article
- Succinylation-annotated genes in AMI: multi-omics and single-cell prioritization of ASGR2 and NPL.Frontiers in cardiovascular medicine · 2026Article
- The mechanism and treatment of protein acylation modification in cardiovascular disease: a narrative review.Frontiers in pharmacology · 2026Review
Corrections and comments
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleThe disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown.
objectiveThis study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM. METHODS AND
resultsThe expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition.
conclusionsSirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.
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