Endogenous mitochondrial hydrogen peroxide regulates neurogenesis during cortical development.

Reactive oxygen species (ROS), particularly superoxide anion (O(2)(•-)) and hydrogen peroxide (H(2)O(2)), originating from mitochondria, are increasingly recognized as critical mediators of physiological signaling and cellular function. While in the adult brain, mitochondrial ROS, specifically mitochondrial H(2)O(2), 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 H(2)O(2) levels and investigate their impact during cortical development. In neurosphere cultures derived from embryonic day 14.5 (E14.5) mCAT mice, reduced mitochondrial H(2)O(2) 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.