Lysine succinylation as a metabolic switch in cardiovascular diseases: Mechanistic insights and therapeutic perspectives

Abstract

Cardiovascular diseases (CVDs) are life-threatening disorders arising from interactions between genetic and environmental factors, imposing a heavy global health burden with high morbidity and mortality. Emerging evidence suggests that dysregulated epigenetic modifications, particularly lysine succinylation, play a critical role in the pathogenesis of CVD. Characterized by the covalent addition of a succinyl group to lysine residues, succinylation dynamically alters the functions of proteins, including those involved in transcriptional regulation, and directly affects energy metabolism, oxidative stress, inflammation, apoptosis, and fibrosis. This modification has been linked to the development of various CVDs, such as atrial fibrillation, myocardial ischemia-reperfusion injury, myocardial infarction, heart failure, aortic aneurysm and dissection, diabetic cardiomyopathy, hypertrophic cardiomyopathy, and atherosclerosis. Its effects on key biological processes contribute to these conditions through multiple mechanisms. This review systematically summarizes current research on the role of succinylation in cardiovascular pathophysiology, with a particular focus on its function as a "metabolic switch" in CVDs. It further highlights the critical role of succinylation in regulating redox homeostasis and maintaining the balance of SIRT5-mediated desuccinylation. By integrating mechanistic insights from preclinical and clinical studies, we aim to provide a comprehensive framework for understanding the multifaceted roles of succinylation in CVDs and to identify potential therapeutic targets for future translational research.

Keywords: Cardioprotection; Cardiovascular diseases; Lysine succinylation; Redox homeostasis; SIRT5.

Fig. 1

Charge and chemical group alterations in lysine succinylation.

Fig. 2

Regulation of succinylation. The mechanisms of succinylation can be divided into two categories: enzymatic modulation and non-enzymatic modulation. CPT1A carnitine palmitoyltransferase 1A, α-KGDHC α-ketoglutarate dehydrogenase complex, KAT2A lysine acetyltransferase 2A, KAT3B lysine acetyltransferase 3B, HAT1 histone acetyltransferase 1, SIRT5 silent information regulator toxin 5, SIRT7 silent information regulator toxin 7, CobB a sirtuin2-like bacterial lysine deacetylase, ScCobB2 Streptomyces coelicolor NAD-dependent protein deacetylase 2, HDAC1/2/3 histone deacetylase 1/2/3, Ksucc lysine succinylation, TCA tricarboxylic acid, SCS succinyl-CoA synthetase, SDH succinate dehydrogenase, MCM methylmalonyl-CoA mutase, PCC propionyl-CoA carboxylase.

Fig. 3

Core mechanisms of Sirt5-mediated desuccinylation in cardioprotection. IDH2 isocitrate dehydrogenase 2, SDH succinate dehydrogenase complex, CPT2 carnitine palmitoyltransferase 2, SOD1 superoxide dismutase 1, IDH2 isocitrate dehydrogenase 2, ACOX1 acyl-CoA oxidase 1, GSTP1 glutathione S-transferase Pi 1, ERO1A endoplasmic reticulum oxidoreductase 1 alpha, HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2, NLRP3 NOD-like receptor family pyrin domain containing 3, CPS1 carbamoyl-phosphate synthetase 1.

Fig. 4

Succinylation regulates intracellular redox status, dictating cardiovascular disease progression or alleviation via a bipolar mechanism centered on redox homeostasis. SIRT5 silent information regulator toxin 5, SDHA succinate dehydrogenase A, HDHA hydroxyacyl-CoA dehydrogenase subunit A, ETC electron transport chain, FAO fatty acid oxidation, O₂·- superoxide anion, TCA tricarboxylic acid, SOD2 superoxide dismutase 2, H₂O₂ hydrogen peroxide, SOD1 superoxide dismutase 1, NADPH nicotinamide adenine dinucleotide phosphate, GSH glutathione, LDHA lactate dehydrogenase A, Txnrd1 thioredoxin reductase 1.

Fig. 5

Panoramic map of the succinylation metabolic network and its association with cardiovascular diseases. Su succinylation, AMPK adenosine 5′-monophosphate -activated protein kinase, SDH succinate dehydrogenase, SIRT5 silent information regulator toxin 5, SIRT7 silent information regulator toxin 7, TOM1 tumour susceptibility gene 1, MG53 mitsugumin 53, α-KGDH α-ketoglutarate dehydrogenase, SCS succinyl-CoA synthetase, ROS reactive oxygen species, RAS renin-angiotensin system, LDHA lactate dehydrogenase A, PKM pyruvate kinase M, SDHA succinate dehydrogenase complex subunit A, CPT2 carnitine palmitoyltransferase 2, LCFA long-chain fatty acid, ECHA enoyl-CoA hydratase A, ATP adenosine triphosphate, EF ejection fraction, NLRP3 NOD-like receptor family pyrin domain containing 3, SUCNR1 succinate receptor 1, DC dendritic cell, PHD prolyl hydroxylase domain, HIF-α hypoxia-inducible factor alpha.