Abstract
Although many factors contribute to cellular differentiation, the role of mitochondria Ca2+ dynamics during development remains unexplored. Because mammalian embryonic epiblasts reside in a hypoxic environment, we intended to understand whether mCa2+ and its transport machineries are regulated during hypoxia. Tissues from multiple organs of developing mouse embryo evidenced a suppression of MICU1 expression with nominal changes on other MCU complex components. As surrogate models, we here utilized human embryonic stem cells (hESCs)/induced pluripotent stem cells (hiPSCs) and primary neonatal myocytes to delineate the mechanisms that control mCa2+ and bioenergetics during development. Analysis of MICU1 expression in hESCs/hiPSCs showed low abundance of MICU1 due to its direct repression by Foxd1. Experimentally, restoration of MICU1 established the periodic cCa2+ oscillations and promoted cellular differentiation and maturation. These findings establish a role of mCa2+ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1.
Highlights
IntroductionMICU1−/− mice that did survive past 1 week show chorealike movement
Restoration of MICU1 established the periodic cCa2+ oscillations and promoted cellular differentiation and maturation. These findings establish a role of mCa2+ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1
Because mitochondrial OXPHOS and energy transduction are mitochondrial Ca2+ dynamics dependent processes, relatively little is known about how the cyclic switch between glycolytic and oxidative metabolism is established during development
Summary
MICU1−/− mice that did survive past 1 week show chorealike movement These data indicate the absence of MICU1 is critical immediately after birth, suggesting MICU1 and mCa2+ signaling to be critical mediators in embryonic to postnatal developmental transition when the demand for oxidative phosphorylation surges. Reconstitution of MICU1 either by Foxd[1] knock down or ectopic expression restores the periodic cytosolic Ca2+ transients that is a prerequisite for cellular differentiation These findings reveal a distinct molecular mechanism underlying the contribution of mitochondrial function in low oxygen tension and the functional role for MICU1 in possibly sensing hypoxia
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