Cardiac nuclear receptors: architects of mitochondrial structure and function

Abstract

The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

Sodium–glucose co‐transporter 2 inhibition with empagliflozin improves cardiac function in non‐diabetic rats with left ventricular dysfunction after myocardial infarction

“…Detailed cardiac and renal analysis of diabetic animal models has revealed that SGLT2i affect mitochondrial morphology and density . Mitochondrial content and respiratory capacity are also significantly reduced in HF, which is tied to diminished expression of the transcription factor PGC‐1α . To determine whether the favourable effects of EMPA on cardiac remodelling were associated with similar recovery of mitochondrial biogenesis, mitochondrial content was quantified by normalizing mtDNA to nDNA.…”

The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure

“…The contributions of the nuclear receptor superfamily to regulating cardiac physiology through ligand-dependent transcriptional regulation have increasingly been recognized (17,27). Although cardiomyocyte nuclear receptors are best known for regulating metabolism, they also participate in numerous other cellular functions (42), including the transcriptional regulation of sarcomeric and Ca 2ϩ -handling genes (8). The retinoic acid-related orphan receptor (ROR) subfamily of nuclear receptors consists of ROR␣, ROR␤, and ROR␥ (NR1F1-NR1F 3) (6,19).…”

Postnatal cardiovascular adaptation

“…Over the first week of life, the heart switches to metabolism of fat via the fatty acid oxidation (FAO) pathway 40. There is a complex signalling mechanism that orchestrates these changes 41. In utero hypoxia-inducible factors (HIF-1α) promote the glucose transporter GLUT-1 and favour glucose metabolism.…”