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

Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2203628119. doi: 10.1073/pnas.2203628119. Epub 2022 Oct 6.


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.

Keywords: 5-aminolevulinic acid; heart failure; mitochondria; oxidative phosphorylation; succinyl-CoA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A
  • Adenosine Diphosphate / metabolism
  • Aminolevulinic Acid
  • Energy Metabolism
  • Glutamates / metabolism
  • Heart Failure* / metabolism
  • Heme / metabolism
  • Humans
  • Ketoglutaric Acids
  • Myocardial Infarction*
  • Oxidative Phosphorylation


  • Acyl Coenzyme A
  • Glutamates
  • Ketoglutaric Acids
  • Heme
  • Adenosine Diphosphate
  • Aminolevulinic Acid
  • succinyl-coenzyme A