Role of Mitochondrial Metabolism in Regulating Species-Specific Developmental Rates

About This Grant

PROJECT SUMMARY/ABSTRACT All mammalian embryos undergo a highly conserved sequence of developmental events, but different species complete this sequence at significantly different speeds. Astonishingly, embryonic development is completed in 15 days in mice, 56 days in humans, and 116 days in elephants. How species-specific developmental rates are set represents a major unanswered question in developmental biology, for which the answer would yield multiple translational opportunities. Acceleration of developmental rate would allow faster production of mature cell types from human induced pluripotent stem cells for cell-based therapies and disease modeling; whereas its deceleration would provide new avenues to halt tumor growth and slow down the aging process. The overarching goal of our research program is to elucidate the regulatory mechanisms that give rise to species-specific developmental speed and develop strategies for its manipulation in translational settings. We previously established an in vitro system that recapitulates the 2-3 fold difference in developmental speed between mouse and human embryos. This system relies on the differentiation of mouse and human pluripotent stem cells to presomitic mesoderm, a cell type that harbors a molecular oscillator known as the segmentation clock. This clock provides a high-resolution, quantitative proxy for developmental speed. Using this system, we recently identified mitochondrial metabolism as an important regulator of developmental speed, with higher mitochondrial respiration giving rise to accelerated development in mouse cells compared to human cells. This regulation was not mediated by mitochondrial ATP production but rather by flux through the electron transport chain independently of oxidative phosphorylation. Our proposed research program consists of three main research directions that will dissect the role of mitochondrial metabolism in determining species-specific developmental rates. The first direction will identify the molecular mechanisms that underpin the connection between mitochondrial respiration and developmental speed. We will evaluate NAD(H) redox homeostasis and pyrimidine biosynthesis as potential rate-limiting factors working downstream of the electron transport chain. Our second research direction will pinpoint the factors that give rise to differential levels of mitochondrial respiration between species. We hypothesize that a combination of differences in mitochondrial ultrastructure and mitochondrial biogenesis are responsible for increased mitochondrial capacity in mouse cells compared to human cells. Finally, our third research direction will test whether mitochondrial metabolism can efficiently regulate developmental speed in more complex developmental settings comprised of multiple lineages. Using genetic tools to boost mitochondrial respiration, we will track the impact of elevated electron transport chain flux on the developmental progression of spatially coupled axial organoids in vitro and as well as mouse embryos in vivo. Our long-term goal is to leverage the insights gleaned from this project to enhance the utility of human pluripotent stem cells for therapeutic applications by devising strategies for the acceleration of developmental rate.