Multiscale Coupling Between Mechanics and Metabolism in Mammalian Oocytes and Embryos

Abstract

Cellular metabolism powers the mechanical processes that shape biological form and function. During mammalian embryogenesis, mechanical forces organize subcellular organelles and tissue architecture, while mitochondrial metabolism fuels these transformations. Both metabolism and mechanics vary across space and time, and disruptions in their organization are associated with infertility and developmental failure. Despite extensive knowledge of the molecular constituents involved, the physical principles that govern how mechanics and metabolism are spatially organized—and how they interact—remain poorly understood. This dissertation investigates the biophysical coupling between these processes across multiple scales, from subcellular organelles to the early embryo. We first study the meiotic spindle in mouse oocytes, a dynamic microtubule-based structure that organizes chromosomes during cell division. Using polarization microscopy, we show that the spindle microtubule network behaves as a nematic liquid crystal. We further find that chromosomes create tactoid-like voids that are spatially ordered within the metaphase plate. We propose that the deformation of the nematic field around these embedded chromosomes induces long-range repulsion, establishing their regular spacing at the metaphase plate. Next, we investigate how mitochondrial metabolism is spatially patterned relative to the meiotic spindle. We demonstrate that mitochondria are intrinsically heterogeneous in protein composition and that their spatial distribution is governed by a two-step mechanism involving actin-driven cytoplasmic flows and metabolism-dependent microtubule binding. A minimal advection-binding model, in which mitochondria are transported by flows but preferentially bind to microtubules based on their metabolic state, quantitatively explains the emergence and maintenance of these metabolic gradients. Finally, we examine the metabolic changes of human embryos from the zygote to the blastocyst stage using fluorescence-lifetime imaging microscopy (FLIM). Using causal inference, we show that metabolic transitions occur independently of morphological progression and the metabolic state of the one-cell zygote predicts subsequent developmental outcomes. Together, these findings help lay the foundation for understanding how energy metabolism and mechanics interact during early mammalian development.