Cardiac nuclear receptors: architects of mitochondrial structure and function

Abstract

The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart.

Figure 1. Developmental changes in myocardial fuel substrate preference are linked to mitochondrial biogenesis and maturation.

The fetal heart relies primarily on glucose (glycolysis) and lactate as preferred fuel substrates. In the postnatal period FAO becomes the primary energy-producing process. This is preceded by a burst of mitochondrial biogenesis and mitophagy, events that are required to build an adult mitochondria network with high oxidative and ATP synthetic capacity.

Figure 2. Cardiac nuclear receptors respond to physiologic cues transduced by the inducible transcriptional coactivator PGC-1α.

Various physiologic stimuli increase cardiac output and energy requirements of the heart. These signals are transmitted through a variety of cellular signaling pathways that regulate PGC-1α expression and/or activity. PGC-1α interacts directly with multiple nuclear receptors and other transcription factors to orchestrate mitochondrial biogenesis and function, including increasing capacity for oxidizing fatty acids. mtDNA, mitochondrial DNA.

Figure 3. Disease etiology–specific perturbations in nuclear receptor signaling result in fuel and energy metabolism derangements in the failing heart.

Deactivation of nuclear receptor signaling contributes to derangements of fuel substrate utilization and mitochondrial energy metabolism during the progression of hypertensive heart disease (the energy-starved heart). Early in the disease process, PPAR signaling becomes inhibited, resulting in a decreased reliance on fatty acids as the preferred fuel substrate. A different phenotype is observed in the setting of diabetes and obesity (the overfed lipotoxic heart). PPAR signaling becomes chronically activated, resulting in increased rates of FAO and exuberant neutral lipid storage. Later in the disease process, a common pathogenic pathway of diminished ERR and PGC-1 signaling leads to decreased mitochondrial energy production and content, resulting in an energy-starved failing heart. This condition manifests as decreased PCr/ATP ratios and impaired contractile efficiency. T2D, type 2 diabetes.