Epigenetic and experimental modifications in early mammalian development: Part I: Mitochondria: potential roles in embryogenesis and nucleocytoplasmic transfer

Abstract

This review examines current understanding of mammalian mitochondria and mitochondrial DNA in the light of new reproductive technologies. Mitochondria are central to ageing, apoptosis, metabolism and many diseases. They are controlled by a dual genome system, with cooperation between endogenous mitochondrial genes and mitochondrial genes translocated to the nucleus over the course of evolution. This translocation has been accompanied by extreme compression of the mitochondrial genome, with little tolerance for mutations or heteroplasmy (multiple genomes). The highly compact mitochondrial genome appears to be maintained by a stringent numerical bottleneck in embryogenesis and oogenesis, followed by clonal expansion from a highly selected subset of precursor molecules. The dual nature of control between nucleus and cytoplasm sets up potential conflicts, which are normally resolved by natural selection. Such potentially opposing interests and mechanisms are probably partly to blame for the poor rates of success in cloning animals by nuclear transfer. The ability to construct cell systems and animal embryos with novel combinations and permutations of nuclear and cytoplasmic genes will provide powerful tools for examining these fundamental biological questions. Clinically, attempts to ‘rescue’ abnormal human oocytes or embryos by cytoplasmic transfer risk complex and unpredictable outcomes emerging from disharmonious nuclear–cytoplasmic interactions.