On the Control of Metabolic Remodeling in Mitochondria of the Failing Heart

Abstract

T he metabolic phenotype of the failing heart may be defined as follows. 1 Metabolism remodels in the failing heart, leading to a loss in energy reserve and the inability to increase ATP supply. Ultimately, this metabolic rigidity leads to a fall in ATP. The likely time line is decreased energy reserve via the phosphotransferase reactions (creatine kinase [CK] and adenylate kinase) leading to increases in ADP and AMP, triggering an increase in glycolysis. Although the contribution of glycolysis to overall ATP synthesis increases at least in the hypertrophied heart, glycolytic reserve is limited. Importantly, as heart failure evolves, ATP synthesis from oxidation of both endogenous and exogenous fatty acids by mitochondria, the major source of ATP in the heart, falls. 2 Article see p 342Remodeling of the failing myocardium is controlled by energy sensors such as AMP that lead to changes in phosphorylation state (as well as other chemical modifications) of many proteins for short-term preservation of ATP and by activation of transcription factors that coordinately control long-term remodeling of entire ATP synthesis and utilizing pathways.Given that the requirement for ATP for all metabolic processes and for cell viability is absolute, a renewed interest in metabolism has led to identification of the molecular links between physiological and metabolic stimuli and the regulation of gene expression in the heart. We not only have identified the metabolic targets of specific nuclear receptors and DNA-binding transcriptional activators but also are beginning to learn how their signals are amplified and sustained to remodel metabolism.Transcription is activated when transcriptional activators, including peroxisome proliferator-activated receptors, estrogen receptors, retinoid receptors, nuclear respiratory factors, and myocyte-enhancing factor-2 (MEF-2) form proteinprotein complexes with the peroxisome proliferator-activated receptor-␥ coactivators, namely PGC-1␣ and ␤, tethering PGC-1s to DNA (Figure). When complexed with the transcription activators, PGC-1s activate genes encoding proteins comprising entire metabolic pathways that control ATP synthesis in mitochondria (fatty acid uptake, ␤-oxidation, oxidative phosphorylation, the Krebs cycle, and electron transport chain), phosphoryl transfer (sarcomeric mitochondrial CK and adenine nucleotide transporter), glucose uptake and utilization, and ATP-utilizing proteins (Figure). The different transcription factors confer specificity of PGC-1s for its genomic targets. Substantial overlap exists, and there is much to learn about the full range of targets. Because of its central role in transcriptional control of metabolism, PGC-1␣ is referred to as a master regulator.PGC-1␣ is itself regulated. For example, the cyclindependent kinases Cdk9 and Cdk7 target PGC-1␣, thereby conferring additional specificity for the transcriptional control of ATP synthesizing and utilizing reactions. Other known regulators of PGC-1␣ in striated muscle include p38 mitogenactivated protein kina...

Metabolomic analysis of two different models of delayed preconditioning

“…On the other hand, PCr and CK activity, central to high-energy phosphates in the cardiomyocyte and the transfer of energy from mitochondria to essential cytosolic ATPase, were significantly increased. This pattern is opposite to that which is observed in failing hearts [27, 28], indicating energy reserve in the repetitive coronary stenosis model can be utilized in situations of ischemic stress or increased contractile demand. Previous studies of the repetitive coronary stenosis model and short term hibernating myocardium have shown upregulation of glucose uptake, increases in anaerobic metabolism and optimization of energy utilization [3, 21, 22, 26, 29, 30].…”

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging

“…It is observed that in both the aging [3,4] and the diseased heart [8][9][10][11][12] relationships between cardiac work rate and concentrations of phosphate metabolites ATP, ADP, and phosphocreatine (CrP) are altered. In heart failure ATP and the CrP/ATP ratio is diminished and [ATP] in myocardium is lower compared to healthy individuals [8,[12][13][14].…”

Astaxanthin Inhibits Mitochondrial Permeability Transition Pore Opening in Rat Heart Mitochondria

“…In mammals, subunit c of F o F 1 -ATP synthase has three isoforms (P1, P2, and P3), encoded by ATP5G1, ATPG2, and ATPG3 genes [12]. Recently, we showed that subunit c of F o F 1 -ATPase might be a structural and/or regulatory component of the mPTP complex, whose activity might be modulated by calcium-dependent phosphorylation [13].Alterations in mitochondrial bioenergetics play important roles in the origin and progression of myocardial ischemia [14], manifesting as inhibition of respiratory complex activity, increased proton leakage from the inner mitochondrial membrane [15], increased ROS production [16], mitochondrial calcium overload [17], and finally, opening of mPTP [18]. During the development of myocardial ischemia, oxygen deprivation alters mitochondrial function and ATP synthesis, causing an important reduction in cardiac ATP production [19].…”

“…Alterations in mitochondrial bioenergetics play important roles in the origin and progression of myocardial ischemia [14], manifesting as inhibition of respiratory complex activity, increased proton leakage from the inner mitochondrial membrane [15], increased ROS production [16], mitochondrial calcium overload [17], and finally, opening of mPTP [18]. During the development of myocardial ischemia, oxygen deprivation alters mitochondrial function and ATP synthesis, causing an important reduction in cardiac ATP production [19].…”