Metabolic Disturbances Involved in Cardiovascular Diseases: The Role of Mitochondrial Dysfunction, Altered Bioenergetics and Oxidative Stress

Abstract

The study of metabolic abnormalities regarding mitochondrial respiration and energy production has significantly advanced our understanding of cell biology and molecular mechanisms underlying cardiovascular diseases (CVDs). Mitochondria provide 90% of the energy required for maintaining normal cardiac function and are central to heart bioenergetics. During the initial phase of heart failure, mitochondrial number and function progressively decline, causing a decrease in oxidative metabolism and increased glucose uptake and glycolysis, leading to ATP depletion and bioenergetic starvation, finally contributing to overt heart failure. Compromised mitochondrial bioenergetics is associated with vascular damage in hypertension, vascular remodeling in pulmonary hypertension and acute cardiovascular events. Thus, mitochondrial dysfunction, leading to impaired ATP production, excessive ROS generation, the opening of mitochondrial permeability transition pores and the activation of apoptotic and necrotic pathways, is revealed as a typical feature of common CVDs. Molecules able to positively modulate cellular metabolism by improving mitochondrial bioenergetics and energy metabolism and inhibiting oxidative stress production are expected to exert beneficial protective effects in the heart and vasculature. This review discusses recent advances in cardiovascular research through the study of cellular bioenergetics in both chronic and acute CVDs. Emerging therapeutic strategies, specifically targeting metabolic modulators, mitochondrial function and quality control, are discussed.

Keywords: cardiac bioenergetics; cardiovascular diseases; glycolysis; metabolic flux analyzers; metabolic reprogramming; mitochondria.

Figure 1

The impact of metabolic reprogramming on PDH activity modulates a series of events within the pulmonary vascular wall, ultimately leading to increased pulmonary vascular resistance and arterial pressure.

Figure 2

Schematic representation of key mechanisms underlying the development of cardiac hypertrophy and ultimately of HF. In fact, altered bioenergetics, along with the decreased number of mitochondria, compromise the efficiency of cardiac contractility.

Figure 3

Bioenergetic dysfunction consequent to atherosclerosis favors plaque instability and the consequent plaque rupture causes known cardiovascular acute events.

Figure 4

Schematic representation of the key metabolic abnormalities shared by common CVDs.