Heart failure (HF) is a leading cause of death and repeated hospitalizations1. HF progression generally involves mitochondrial dysfunction2-4. However, how mitochondria react to chronic HF remains unclear. Here, we show the molecular basis of mitochondrial dysfunction in chronic HF, which is characterized by altered succinyl-CoA metabolism. In myocardial mitochondria of coronary ligated mice, heme synthesis and ketolysis, and enzymes using succinyl-CoA in these events were upregulated, and enzymes synthesizing succinyl-CoA at the tricarboxylic acid (TCA) cycle were also increased. Intriguingly, the ADP-specific, but not the GDP-specific, subunit of succinyl-CoA synthetase, which uses succinyl-CoA in the TCA cycle, was decreased. Myocardial succinyl-CoA levels were significantly reduced in chronic HF, impairing mitochondrial oxidative phosphorylation (OXPHOS). Consequently, the administration of 5-aminolevulinic acid (ALA)5, an intermediate in the pathway from succinyl-CoA to heme synthesis, prevented HF progression in mice. Previous reports also support the presence of succinyl-CoA metabolism abnormalities in HF patients6,7. Our results indicated that changes in succinyl-CoA usage in various energy production systems in myocardial mitochondria is characteristic to chronic HF, and that although similar alterations occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in HF. Moreover, nutritional interventions compensating the metabolic changes are likely to provide effective methods to treat HF.