Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart

Abstract

Despite significant progress in cardiovascular medicine, myocardial ischemia and infarction, progressing eventually to the final end point heart failure (HF), remain the leading cause of morbidity and mortality in the USA. HF is a complex syndrome that results from any structural or functional impairment in ventricular filling or blood ejection. Ultimately, the heart's inability to supply the body's tissues with enough blood may lead to death. Mechanistically, the hallmarks of the failing heart include abnormal energy metabolism, increased production of reactive oxygen species (ROS) and defects in excitation-contraction coupling. HF is a highly dynamic pathological process, and observed alterations in cardiac metabolism and function depend on the disease progression. In the early stages, cardiac remodeling characterized by normal or slightly increased fatty acid (FA) oxidation plays a compensatory, cardioprotective role. However, upon progression of HF, FA oxidation and mitochondrial oxidative activity are decreased, resulting in a significant drop in cardiac ATP levels. In HF, as a compensatory response to decreased oxidative metabolism, glucose uptake and glycolysis are upregulated, but this upregulation is not sufficient to compensate for a drop in ATP production. Elevated mitochondrial ROS generation and ROS-mediated damage, when they overwhelm the cellular antioxidant defense system, induce heart injury and contribute to the progression of HF. Mitochondrial uncoupling proteins (UCPs), which promote proton leak across the inner mitochondrial membrane, have emerged as essential regulators of mitochondrial membrane potential, respiratory activity and ROS generation. Although the physiological role of UCP2 and UCP3, expressed in the heart, has not been clearly established, increasing evidence suggests that these proteins by promoting mild uncoupling could reduce mitochondrial ROS generation and cardiomyocyte apoptosis and ameliorate thereby myocardial function. Further investigation on the alterations in cardiac UCP activity and regulation will advance our understanding of their physiological roles in the healthy and diseased heart and also may facilitate the development of novel and more efficient therapies.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

“…We found that expression of most genes involved in ROS generation/scavenging did not show significant difference in either of the mutants compared with littermate controls. Differences in gene expression (P < 0.001 compared with littermate controls) were observed only for extracellular superoxide dismutase (Sod 3) (68) and thioredoxin-interacting protein (Txnip) (69) mRNAs in TnT mutants, and uncoupling protein mRNAs (Ucp1, Ucp3) (70) in MyHC mutants (Supplemental Figure 2 and Supplemental Table 2). …”

Cell Death and Heart Failure in Obesity: Role of Uncoupling Proteins

“…In animal model of heart failure induced by pressure overload induced by constriction of the ascending aorta, the expression of UCP2 and UCP3 is downregulated and an increase of ROS generation is enhanced to induce cardiac cell hypertrophy [38, 44]. However this model does not involve FFAs-induced upregulation of UCPs that may protect cell from hypertrophy and dysfunction.…”

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

“…Inappropriate production of oxygen-free radicals in mitochondria, overwhelming the antioxidant defense systems, and the resulting oxidative damage to mitochondrial DNA and mitochondrial proteins have long been recognized as playing a causative role in the development and progression of cardiac remodeling and dysfunction. [16][17][18] However, we cannot exclude that regulation of nicotinamide adenine dinucleotide phosphate oxidase-generated superoxide, as a nonmitochondrial source of ROS, may also be involved in the cardioprotection of PETN against maladaptive remodeling.…”

“…18,19,[30][31][32] Altered mitochondrial redox balance may decrease the expression of UCP3, whereas mechanical unloading restored UCP3 in the failing human heart. 30,32 Genetic deletion of UCP3 promoted mitochondrial dysfunction and ROS production, leading to adverse cardiac remodeling after MI.…”