Endogenous mitochondrial hydrogen peroxide regulates neurogenesis during cortical development

Reactive oxygen species (ROS), particularly superoxide anion (O₂^•-) and hydrogen peroxide (H₂O₂), originating from mitochondria, are increasingly recognized as critical mediators of physiological signaling and cellular function. While in the adult brain, mitochondrial ROS, specifically mitochondrial H₂O₂, modulate metabolism and sustains cognitive processes, their role in the developing cerebral cortex remains undefined. Here, we leverage a knock-in mouse model constitutively expressing mitochondrially targeted catalase (mCAT) to attenuate mitochondrial H₂O₂ levels and investigate their impact during cortical development. In neurosphere cultures derived from embryonic day 14.5 (E14.5) mCAT mice, reduced mitochondrial H₂O₂ altered glutathione redox homeostasis and glucose metabolism leading to suppressed progenitor cell proliferation, without compromising viability. In vivo, neural progenitor cell (NPC) proliferation, neuronal differentiation and cortical layering were disrupted starting at gestational day E15. Together, these data uncover a physiological role for mitochondrial hydrogen peroxide in orchestrating neural precursor proliferation and differentiation, ultimately influencing mammalian cerebral cortex formation.