NIH grant: Role of Mitochondrial Metabolism in Regulating Species-Specific Developmental Rates (1R35GM165865-01)

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NIH grant 1R35GM165865-01: Role of Mitochondrial Metabolism in Regulating Species-Specific Developmental Rates
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Margarete  Diaz Cuadros. Award: $453750.
Start: 2026-08-01T00:00:00.
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.

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