Hypoxia signaling controls postnatal changes in cardiac mitochondrial morphology and function

Abstract

Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined.Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation.

Postnatal Hyperoxia Exposure Durably Impairs Right Ventricular Function and Mitochondrial Biogenesis

“…Thus, a direct effect of hyperoxia on the immature RV cardiomyocyte should be considered. Although postnatal Hx is known to acutely worsen mitochondrial dysfunction and oxidative stress in the lung, relative hyperoxia, as is encountered at birth into a normoxic environment, is critical to initiate neonatal cardiac mitochondrial biogenesis and oxidative metabolism within the LV (35)(36)(37)(38). However, (normalized to vinculin) after Hx, all key elements of mitochondrial structure.…”

Developmental plasticity of mitochondrial function in American alligators,Alligator mississippiensis

“…Structural and functional remodeling of mitochondria during development is a well-established phenomenon in mammals and is thought to occur in response to the growing energetic demands of development (54). Mammalian embryonic mitochondria undergo considerable structural and functional changes during midpregnancy coinciding with a switch from anaerobic glycolytic metabolism to oxidative phosphorylation (3).…”

“…Nevertheless, the oxidative capacities of mammalian mitochondria from late-gestation fetuses are considerably lower than those from juvenile or adult mitochondria (51). After birth, the rise in ambient oxygen levels, metabolic rate, cardiac output, and energy demands requires an upregulation of mitochondrial biogenesis, a switch from glycolysis to β-oxidation of lipids (which generate larger amounts of ATP per unit of substrate), and activation of nuclear and mitochondrial gene expression (47, 51, 54). The mechanisms underlying postnatal metabolic remodeling in mammals are incompletely understood, but recent evidence suggests mitochondrial biogenesis is upregulated as a consequence of Pgc1α/β expression (46), and the switch in substrate utilization occurs via hypoxia-inducible factor (HIF) signaling (54).…”

A time to reap, a time to sow: Mitophagy and biogenesis in cardiac pathophysiology

“…This is manifest at the transition from the fetal hypoxic state to the postnatal aerobic environment, when HIF signaling is lost, thereby favoring mitochondrial fusion and mitochondrial biogenesis [169]. During cardiac hypertrophy in response to aortic banding, mitochondrial dysfunction and decreased biogenesis were noted [170].…”