Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure

Abstract

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases

“…Dysfunction of OXPHOS is considered as one of the main causes of CVDs [64]. In chronic HF patients, reduced succinyl-CoA levels in myocardial mitochondria cause decreased OXPHOS [65]. In a study of human thoracic aortic aneurysm tissue, when mitochondrial OXPHOS related gene expression is inhibited, although chromatin OXPHOS related genes are increased, the ATP production is still insufficient to maintain contractile activity in human aortic smooth muscle cells (HAoSMCs) [41].…”

Exopolysaccharide-Producing Lacticaseibacillus rhamnosus Space Mutant Improves the Techno-Functional Characteristics of Fermented Cow and Goat Milks

“…Its functions in the pyruvate oxidation and fatty acid synthesis/oxidation in the tricarboxylic acid cycle are noteworthy, and 90% of the energy required for life is provided by coenzyme A, which takes part in a number of bodily metabolic processes . The increase in the succinyl-CoA level can improve the mitochondrial oxidative phosphorylation capacity and effectively alleviate chronic heart failure . In addition, nicotinamide ribose, a derivative of vitamin B3, has been shown to enhance oxidative metabolism and prevent metabolic abnormalities induced by high-fat diet .…”

“…51 The increase in the succinyl-CoA level can improve the mitochondrial oxidative phosphorylation capacity and effectively alleviate chronic heart failure. 52 In addition, nicotinamide ribose, a derivative of vitamin B3, 53 high-fat diet. 54 Alcohols in yogurt can combine with free amino acids to form esters.…”

Ketones and the Heart: Metabolic Principles and Therapeutic Implications

“…Succinyl-CoA is siphoned for heme synthesis and by SCOT during ketolysis. 89 Consumption of succinyl-CoA was increased following MI, potentially due to increased ketone oxidation. Restoration of succinyl-CoA levels with 5-aminolevulinic acid improved oxidative phosphorylation capacity and reduced HF after MI.…”