Abstract
During cardiac development, cellular energy production evolves dramatically. Mechanisms that control these changes and activation of electron transport chain (ETC) remain unclear. Our aim was to provide a comprehensive analysis of mitochondrial biology and bioenergetics in the developing wild type heart for use in experimental models, such as mice, in which the mitochondrial protein, cyclophilin D (CyPD), was deleted. Mouse hearts were harvested from wild type and CyPD null hearts throughout development and examined by electron microscopy, liquid chromatography/mass spectrometry, oxygen consumption and enzyme assays, gel electrophoresis/immunoblotting, and calcium retention capacity (CRC). As the heart develops, myocyte size and mitochondrial number, size, and complexity increases with transitions at the end of the embryonic period and immediately after birth. Metabolomic profiling demonstrated changes in glycolysis, the TCA cycle, and redox state during development and these changes may facilitate proliferation in the neonatal heart. Activation of ETC complexes I, III, IV, and V occurs in the mid-embryonic period, while assembly of ETC supercomplexes begins at the late embryonic period. In contrast, complex II activity is relatively stable during development. CRC assays demonstrated a gradual decrease in the probability of mPTP opening during development, and while CyPD expression increased, its specific enzymatic activity decreased. For most assays tested, these metabolic transitions occurred earlier in development in CyPD null mice. In conclusion, the developing heart undergoes changes in cellular bioenergetics with two transitions at the end of the embryonic period and immediately after birth. Deletion of CyPD causes these transitions to occur earlier in development, suggesting that CyPD and closure of the mPTP controls mitochondrial activation and bioenergetics during cardiac development.
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