Abstract
Chronic intrauterine hypoxia is a programming stimulus of cardiovascular dysfunction. While the fetal heart adapts to the reduced oxygenation, the offspring heart becomes vulnerable to subsequent metabolic challenges as an adult. Cardiac mitochondria are key organelles responsible for an efficient energy supply but are subject to damage under hypoxic conditions. We propose that intrauterine hypoxia alters mitochondrial function as an underlying programming mechanism of contractile dysfunction in the offspring. Indices of mitochondrial function such as mitochondrial DNA content, Complex (C) I-V expression, and CI/CIV enzyme activity were measured in hearts of male and female offspring at 90 days old exposed to prenatal hypoxia (10.5% O2) for 14 d prior to term (65 d). Both left ventricular tissue and cardiomyocytes exhibited decreased mitochondrial DNA content, expression of CIV, and CI/CIV activity in male hearts. In female cardiomyocytes, hypoxia had no effect on protein expression of CI-CV nor on CI/CIV activity. This study suggests that chronic intrauterine hypoxia alters the intrinsic properties of select respiratory complexes as a programming mechanism of cardiac dysfunction in the offspring. Sex differences in mitochondrial function may underlie the increased vulnerability of age-matched males compared to females in cardiovascular disease and heart failure.
Highlights
In adult hearts, the mitochondria play an important role in contractile function in generating 90% of ATP via oxidative phosphorylation [1, 2]
We propose that mitochondrial programming of cardiomyocytes of fetal hearts is initiated in utero by prenatal hypoxia as an underlying cause of mitochondrial and contractile dysfunction in the adult
This study presents evidence that prenatal HPX induces alterations in cardiac mitochondria that are manifested in offspring hearts as decreased mitochondrial content, decreased CIV expression, and decreased CI/CIV activity
Summary
The mitochondria play an important role in contractile function in generating 90% of ATP via oxidative phosphorylation [1, 2]. In contrast to the adult, the early fetal heart relies predominantly on glycolysis for its energy supply because (1) glucose is a major energy substrate, (2) the glycolytic enzymes are upregulated via hypoxia signaling [3], and (3) oxidative phosphorylation is inefficient, resulting from a less organized ultrastructure within the mitochondria and in association with the myofibrils [4, 5]. The adult heart relies predominantly on the TCA cycle and β-oxidation to provide NADH and FADH2 to the electron transport chain for oxidative phosphorylation. Electrons are transported from CI to Oxidative Medicine and Cellular Longevity
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