Dramatic maturational changes occur in cardiac energy metabolism during cardiac development, differentiation, and postnatal growth. These changes in energy metabolism have important impacts on the ability of the cardiomyocyte to proliferate during early cardiac development, as well as when cardiomyocytes terminally differentiate during later development. During early cardiac development, glycolysis is a major source of energy for proliferating cardiomyocytes. As cardiomyocytes mature and become terminally differentiated, mitochondrial oxidative capacity increases, with fatty acid beta-oxidation becoming a major source of energy for the heart. The increase in mitochondrial oxidative capacity seems to coincide with a decrease in the proliferative ability of the cardiomyocyte. The switch from glycolysis to mitochondrial oxidative metabolism during cardiac development includes both alterations in the transcriptional control and acute alterations in the control of each pathway. Interestingly, if a hypertrophic stress is placed on the adult heart, cardiac energy metabolism switches to a more fetal phenotype, which includes an increase in glycolysis and decrease in mitochondrial fatty acid beta-oxidation. In this article, we review the impact of alterations in energy substrate metabolism on cardiomyocyte proliferation, differentiation, and postnatal maturation.

Energy Metabolic Phenotype of the Cardiomyocyte During Development, Differentiation, and Postnatal Maturation

Mitochondria are found in all eukaryotic cells and contain their own genome (mitochondrial DNA or mtDNA). Unlike the nuclear genome, which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo is derived almost exclusively from the egg; that is, it is of maternal origin. Mutations in mtDNA contribute to a diverse range of currently incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle-chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg. The reconstructed oocytes with the mitochondrial replacement were capable of supporting normal fertilization, embryo development and produced healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from the spindle donors whereas mtDNA came from the cytoplast donors. No contribution of spindle donor mtDNA was detected in offspring. Spindle replacement is shown here as an efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines. This approach may offer a reproductive option to prevent mtDNA disease transmission in affected families.

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Mitochondrial gene replacement in primate offspring and embryonic stem cells

Mitochondrial function in the human oocyte and embryo and their role in developmental competence.

Mitochondria have long been known to be the powerhouses of the cell but they also contribute to redox and Ca2+ homeostasis, provide intermediary metabolites and store proapoptotic factors. Mitochondria have a unique behavior during development. They are maternally transmitted with little (if any) paternal contribution, and they originate from a restricted founder population, which is amplified during oogenesis. Then, having established the full complement of mitochondria in the fully grown oocyte, there is no further increase of the mitochondrial population during early development. The localization of mitochondria in the egg during maturation and their segregation to blastomeres in the cleaving embryo are strictly regulated. Gradients in the distribution of mitochondria present in the egg have the potential to give rise to blastomeres receiving different numbers of mitochondria. Such maternally inherited differences in mitochondrial distribution are thought to play roles in defining the long-term viability of the blastomere in some cases and embryonic axes and patterning in others. Mitochondria may also regulate development by a number of other means, including modulating Ca2+ signaling, and the production of ATP, reactive oxygen species, and intermediary metabolites. If the participation of mitochondria in the regulation of sperm-triggered Ca2+ oscillations is now well established, the role of other properties of mitochondrial function during development remain largely unexplored probably due to the difficulty of accessing the mitochondrial compartment in an embryo. Maintaining a functional complement of maternally derived mitochondria is vital for the early embryo. Mitochondrial dysfunction may not only compromise developmental processes but also trigger apoptosis in the embryo. This dual role for mitochondria (to maintain life or to commit to cell death) may well represent a quality control system in the early embryo that will determine whether the embryo proceeds further into development or is quickly eliminated.

The role of mitochondrial function in the oocyte and embryo.

In humans, normal healthy children are regularly produced through fertilization of fresh oocytes with fresh spermatozoa.However, asynchrony between oocytes and spermatozoa, especially when aged oocytes are fertilized by fresh or senescent spermatozoa,will not only affect the rate of fertilization and pre- and post-implantation embryo development but also the life of the offspring. As manyfailures in assisted reproduction technologies (ART) are related to oocyte aging, new methods are needed to control oocyte aging to beneﬁtmodern ART.

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Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility

Mitochondria play a vital role in the metabolism of energy-containing compounds in the oocyte cytoplasm to provide adenosine trisphosphate for fertilization and preimplantation embryo development. In this study, ratiometric confocal microscopy with the mitochondrion-specific membrane potential-sensitive fluorescence dye JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide) was used to measure the activity of mitochondria in human oocytes and developing preimplantation embryos. Mitochondria in oocytes and embryos were characterized by distinct localized aggregation patterns. These patterns however did not determine localized regions of heterogeneity in mitochondrial activity. Mitochondrial activity was analysed during oocyte maturation and after fertilization. The activity of mitochondria in fresh metaphase II oocytes was negatively correlated with maternal age. This trend continued when the activity of developing embryos was analysed. Mitochondrial activity was strongly correlated with the rate of embryo development on day 3 after fertilization, but not on day 2. Partial regression analysis showed that the rate of cleavage of preimplantation embryos was more highly correlated with embryo mitochondrial activity than maternal age. These data suggest that the efficiency of mitochondrial respiration in oocytes and preimplantation embryos is closely correlated with the programmed rate of embryo development, and suggest that maternal age further influences this factor. The loss of mitochondrial activity in oocytes obtained from ageing couples may therefore contribute to lower embryo development and pregnancy rates observed during cycles of IVF.

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Maria Laura Pisaturo

Papers

Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos