Prenatal Corticosterone Exposure Reprograms Brain Cell Mitochondria, Prioritizing Membrane Potential Over Energy Production

Mitochondrial bioenergetics plays a fundamental role in neuronal development and function. Previous research has shown that when rats are exposed to the stress hormone corticosterone before birth, their offspring (Corti. Pups) exhibit delayed neurodevelopment and deficits in synaptic plasticity, showing attention deficit hyperactivity disorder (ADHD)-like behaviors. However, the underlying mitochondrial metabolic adaptations remained unclear.

This study investigated mitochondrial function and metabolic remodeling in prefrontal cortex neurons of these Corti. Pups, focusing on oxidative phosphorylation, calcium handling, and redox balance. Researchers assessed neuronal viability, reactive oxygen species (ROS) production, and oxygen consumption rate (OCR) through experiments conducted in both neuron-glia co-culture and neuron-only conditions. Further investigation involved evaluating electron transport chain (ETC) activity, mitochondrial membrane potential (MMP), and mitochondrial Ca²⁺ uptake in purified isolated mitochondria. The findings revealed that Corti. Pup neurons exhibited increased vulnerability to glutamate-induced excitotoxicity in the absence of glial support.

Intriguingly, despite reduced ROS production, these neurons showed elevated mitochondrial oxygen consumption and proton leak, coupled with decreased non-mitochondrial oxygen consumption and reduced ETC complex activity. Even more surprising was the observation that mitochondrial membrane potential (MMP) remained elevated despite ETC dysfunction, while mitochondrial Ca²⁺ uptake was suppressed. These observations indicate mitochondrial metabolic reprogramming. As lead author Amarsanaa notes in the paper, 'These features indicate mitochondrial metabolic reprogramming, prioritizing MMP maintenance over ATP synthesis,' effectively prioritizing the maintenance of MMP over the generation of ATP, the cell's primary energy currency. The observed mitochondrial inefficiency and compensatory adaptations may impair energy production, contributing to delayed neuronal development in Corti.Pups. These findings suggest that mitochondrial dysfunction and metabolic remodeling play central roles in the pathogenesis of neurodevelopmental disorders such as ADHD.