Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC_mito), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TC_nuc). We demonstrated that E-TC_mito repurposes molecules traditionally associated with E-TC_nuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TC_mito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TC_mito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.