Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities

Abstract

Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.

Keywords: cardiac disease; cardiac rehabilitation; cellular recovery; electron transport chain; heart failure; inflammation; mitochondria; oxidative stress.

Figure 1

Pathophysiological mechanisms dependent on mitochondrial dysfunction in HF. Figure legend: Mitochondrial dysfunction is a typical feature of HF, being either a consequence or a cause of disease, and it leads to several molecular effects. The most relevant cellular pathways that are dysregulated in this condition, ending up as increased ROS level, are represented in the figure. The consequent cellular damage aggravates the disease contributing to HF progression. Abbreviations: ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; ETC, electron transport chain; mPTP, mitochondrial permeability transition pore; NCLX, mitochondrial Na⁺/Ca²⁺ exchanger; OXPHOS, oxidative phosphorylation system; ROS, reactive oxygen species.