Members of the Bcl-2 protein family modulate outer mitochondrial membrane permeability to control apoptosis1 ,2 . However, these proteins also localize to the endoplasmic reticulum (ER), the functional significance of which is controversial 3, 4. Here we provide evidence that anti-apoptotic Bcl-2 proteins regulate the inositol 1,4,5-trisphosphate receptor (InsP 3 R) ER Ca 2+ release channel resulting in increased cellular apoptotic resistance and enhanced mitochondrial bioenergetics. Anti-apoptotic Bcl-X L interacts with the carboxyl terminus of the InsP 3 R and sensitizes single InsP 3 R channels in ER membranes to low [InsP 3 ], enhancing Ca 2+ and InsP 3 -dependent regulation of channel activity in vitro and in vivo, reducing ER Ca 2+ content and stimulating mitochondrial energetics. The proapoptotic proteins Bax and tBid antagonize this effect by blocking the biochemical interaction of Bcl-X L with the InsP 3 R. These data support a novel model in which Bcl-X L is a direct effector of the InsP 3 R, increasing its sensitivity to InsP 3 and enabling ER Ca 2+ release to be more sensitively coupled to extracellular signals. As a consequence, cells are protected against apoptosis by a more sensitive and dynamic coupling of ER to mitochondria through Ca 2+ -dependent signal transduction that enhances cellular bioenergetics and preserves survival.A central feature of molecular models of apoptosis is the control of outer mitochondrial membrane permeability by Bcl-2-related proteins. The pro-apoptotic Bcl-2-related proteins Bax and Bak are required to initiate cytochrome c release from mitochondria in response to diverse apoptotic stimuli 1,5 . Anti-apoptotic properties of Bcl-2 and Bcl-X L have been attributed to their ability to antagonize Bax/Bak by forming heterodimers that prevent their oligomerization and apoptosis initiation 6 . Pro-and anti-apoptotic Bcl-2 proteins also localize to the ER 3,7 , and it is now recognized that the ER has an important role in regulating apoptosis 8,9 . The ER is thought to contribute to apoptosis through its role as the principle Ca 2+ storage organelle in cells [8][9][10][11] . At physiological levels, Ca 2+ released from the ER during

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302–367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. In mice, loss of miR302–367 led to decreased cardiomyocyte proliferation during development. In contrast, increased miR302–367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal reexpression of miR302–367 reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. However, long-term expression of miR302–367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. This limitation can be overcome by transient systemic application of miR302–367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA-based therapeutic approaches to promote mammalian cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation.

Rationale: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell–derived cardiac myocytes. Objective: To delineate transcriptional drivers of cardiac maturation. Methods and Results: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell–derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. Conclusions: ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.

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...