Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart

Abstract

The heart is an omnivore organ that requires constant energy production to match its functional demands. In the adult heart, adenosine-5'-triphosphate (ATP) production occurs mainly through mitochondrial fatty acid and glucose oxidation. The heart must constantly adapt its energy production in response to changes in substrate supply and work demands across diverse physiologic and pathophysiologic conditions. The cardiac myocyte maintains a high level of mitochondrial ATP production through a complex transcriptional regulatory network that is orchestrated by the members of the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family. There is increasing evidence that during the development of cardiac hypertrophy and in the failing heart, the activity of this network, including PGC-1, is altered. This review summarizes our current understanding of the perturbations in the gene regulatory pathways that occur during the development of heart failure. An appreciation of the role this regulatory circuitry serves in the regulation of cardiac energy metabolism may unveil novel therapeutic targets aimed at the metabolic disturbances that presage heart failure. This article is part of a Special Issue entitled:Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.

Figure 1

Divergent substrate utilization in the hypertensive, hypertrophic and insulin resistant, diabetic hearts. The specific etiology of heart disease promotes different substrate utilization in the cardiac myocyte. Cardiac hypertrophy frequently associated with hypertension and ischemia promotes glucose utilization while obesity and diabetes favors increased fatty acid oxidation (FAO). PPARα activity is central to the control of FAO and its modulation in hypertrophy (down) or diabetes (up) contributes to the observed changes in fuel source. However, both substrate switches eventually lead to mitochondrial dysfunction contributing to the progression of clinical heart failure. LVH, left ventricular hypertrophy; PPARα, peroxisome proliferator- activated receptor alpha; PCr, phosphocreatine; TAG, triacylglycerol.

Figure 2

Mechanistic model of myocardial lipid accumulation relevant to obesity-related forms of heart failure that occur in the diabetic heart. There is an influx of fatty acids into the cardiac myocyte in the setting of obesity and insulin resistance. Excess intracellular fatty acids are stored as triglycerides or can act as activating ligands for PPARα. At least in the early stages of insulin resistance, activation of PPARα results in increased mitochondrial fatty acid β-oxidation. However, PPARα also activates fatty acid import pathways, including CD36, to begin a vicious cycle of increased import and storage of fatty acids. Eventually, PGC-1 levels fall and mitochondrial and cardiac dysfunction ensues. DGAT1, diacylglycerol acyltransferase 1; SCD1, stearoyl-CoA desaturase 1; TAG, triacylglycerol; PPARα, peroxisome proliferator- activated receptor alpha; PGC-1, PPARγ coactivator-1

Figure 3

PGC-1α control of cardiac mitochondrial function. PGC-1α integrates signals from physiologic stimuli as well as upstream modulators such as sirtuins (SIRT) and AMPK. Direct interaction with multiple transcription factors drives expression of proteins involved in all aspects of mitochondrial function. SIRT1, sirtuin 1; AMPK, AMP-activated protein kinase; PGC-1α, PPARγ coactivator-1 alpha; PPARα, peroxisome proliferator-activated receptor alpha; RXR, retinoid X receptor; ERR, estrogen-related receptor; NRF, nuclear respiratory factor; ETC, electron transport chain; OXPHOS, oxidative phosphorylation.