The Role of NADH Redox Metabolism and Mitochondrial Complex I in Embryonic Development: A Focus on Maternal and Neonatal Care

Abstract

The quiescent to transcriptionally active embryonic transition is one of the most impressive biological developmental biology changes. The major feature of this process is the complex interconnection between mitochondrial metabolism, especially NADH redox processes and Complex I activity and the development of transcriptional competence via embryonic genome activation (EGA). This is an extensive review of mechanistic interactions among mitochondrial energy metabolism, redox signaling and chromatin remodeling which together coordinate the maternal-to-zygotic transition. We discuss the effects of changes in NADH/NAD+ ratio in epigenetic change, especially the control of sirtuins and other enzymes dependent on NAD+, and developmental progression through a metabolic checkpoint of Complex I activity. Moreover, we mention the impact of reactive oxygen species (ROS) production by Complex I in cellular signaling pathways which control cell fate decisions, pluripotency maintenance, and differentiation. Through recent developments in single-cell metabolomics and live imaging technology, the subsequent levels of spatial and temporal heterogeneity of mitochondrial activity during early embryogenesis have been shown, which does not fit the extant models of homogeneous metabolic reprogramming. The review is a synthesis of existing knowledge regarding the role of mitochondrial metabolism, especially NADH redox metabolism and Complex I activity, in being a key regulator of embryonic genome activation and cellular state transitions, which have implications to assisted reproductive technologies, regenerative medicine, and our developmental disorder biology.