Targeting Mitochondrial Metabolism to Save the Failing Heart

Abstract

Despite considerable progress in treating cardiac disorders, the prevalence of heart failure (HF) keeps growing, making it a global medical and economic burden. HF is characterized by profound metabolic remodeling, which mostly occurs in the mitochondria. Although it is well established that the failing heart is energy-deficient, the role of mitochondria in the pathophysiology of HF extends beyond the energetic aspects. Changes in substrate oxidation, tricarboxylic acid cycle and the respiratory chain have emerged as key players in regulating myocardial energy homeostasis, Ca²⁺ handling, oxidative stress and inflammation. This work aims to highlight metabolic alterations in the mitochondria and their far-reaching effects on the pathophysiology of HF. Based on this knowledge, we will also discuss potential metabolic approaches to improve cardiac function.

Keywords: heart failure; heart failure treatment; metabolism; mitochondria.

Figure 1

Proposed mechanisms linking mitochondrial metabolic changes to major defects in the failing heart. The oxidation of both fatty acids and pyruvate is impaired. There is also a shift towards cataplerosis to recruit amino acids for hypertrophic growth. Both changes result in depletion of TCA cycle pool. Furthermore, OXPHOS is disturbed, and ATP is increasingly consumed by protein synthesis. All these maladaptations culminate in ATP deficiency. Perturbations in OXPHOS foster mitochondrial ROS production. The carboxylation of pyruvate consumes NADPH and therefore impedes antioxidative defense. The resulting oxidative stress promotes inflammation and impairs Ca²⁺ handling. Ca²⁺ homeostasis may also be affected by ATP deficiency.