Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Abstract

f Almost all cellular functions are powered by a continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors estrogen-related receptor ␣ (ERR␣) and ERR␥ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERR␣ and ERR␥ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERR␣ and ERR␥ influence major cardiomyocyte energy consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis, and conduction genes. Mice lacking both ERR␣ and cardiac ERR␥ develop severe bradycardia, lethal cardiomyopathy, and heart failure featuring metabolic, contractile, and conduction dysfunctions. These results illustrate that the ERR transcriptional pathway is essential to couple cellular energy metabolism with energy consumption processes in order to maintain normal cardiac function. E very cell's own survival and vital functions are supported by energy-generating metabolic pathways. The cellular energy supply and demand must be coordinated, and an imbalance results in cellular dysfunctions and diseases from heart failure to obesity (1, 2). Although the regulation of cellular energy production and consumption individually are focuses of intensive research, it is little understood how these two processes are coordinated. One possible mechanism lies at the level of transcription where the expression of genes critical in both cellular energy production and utilization processes can be regulated in an orchestrated manner. However, such transcription coordinators that directly regulate multiple energy-generating cellular metabolic pathways and energy-consuming cellular functions remain to be established.The heart offers an ideal system for studying coordination of energy production and consumption. It continuously pumps blood to all the organs, involving energy-demanding processes such as myocardial contraction and electrical conduction (3). Accordingly, cardiomyocytes maintain an exceedingly high metabolic rate and depend on vigorous fatty acid oxidation (FAO), oxidative phosphorylation (OxPhos), and dynamic mitochondrial networks to generate energy that supports these functions (4, 5). Indeed, defects in cardiomyocyte metabolism and mitochondrial function are underlying causes of, or are associated with, many cardiac diseases, including cardiomyopathy and heart failure, that affect millions of people (6-9).Nuclear receptors (NRs) are ligand-activated transcription factors with important roles in both physiological and pathological settings (10-12). Among the 48 NRs in the human genome, several NRs and their coactivators have been identified as key regulators of cardiac metabolism (13-16). In particular, recent work has revealed...

Cardiac nuclear receptors: architects of mitochondrial structure and function

“…ERRγ is also necessary for normal cardiac function, as genetic deletion results in perinatal lethality with a failure to transition to oxidative metabolism in heart (51). Finally, postnatal and cardiac-specific deletion of Esrrg on an Esrra-null background results in a lethal cardiomyopathy characterized by abnormalities in mitochondrial structure and function and reduced energy production capacity (52). These results underscore the central role of ERRs in the broad control of cardiac mitochondrial function and also highlight the functional overlap and redundancy of ERRα and -γ in the mammalian heart.…”

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…Ppars have long been known to induce metabolic genes that function within mitochondria. Esrrs contribute to the expression of nuclear encoded mitochondrial gene expression and have been found to be functionally relevant in the postnatal mitochondrial biogenesis in the heart (8,38). The Errα-binding motif TGACCTY was highly enriched in downregulated gene promoters, while motifs for Tcf3 and Lef1, among others, were enriched in both upregulated and downregulated promoters ( Figure 8B and Supplemental Tables 7 and 8).…”

“…Errs have broader target specificity, as Errα and Errγ share promoter-binding motifs that are present in energy uptake and utilization, Ca 2+ handling, and contractile genes (6). Cardiac ablation of the genes encoding Errα, Errγ, and Pgc1 lead to cardiac dysfunction, particularly under pathological stress (7)(8)(9). MAPKs respond to growth factors (i.e., extracellular-regulated kinases Erk1 and Erk2), stresses (p38), or both (Erk5) (10) and regulate gene Widespread changes in cardiac gene expression occur during heart failure, yet the mechanisms responsible for coordinating these changes remain poorly understood.…”

There and back again: The journey of the estrogen-related receptors in the cancer realm

“…Physiological studies validated the importance of the ERRs in regulating energy balance in vivo: experiments in ERRa-null mice demonstrated that ERRa is required to generate energy required to respond to physiological and pathological stresses in various tissues, but is not essential for basal cellular energy needs [35][36][37][38][39][40]. Conversely, ERRg is necessary to direct and maintain the metabolic switch in the fetal heart at birth from an energy dependence on primarily carbohydrates during development to fatty acid oxidation in the postnatal heart [41,42]. Meanwhile, the development of functional genomics technologies were pivotal in understanding the consequences of ERR transcriptional activity.…”