Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice
Wenwen Li, Jiarui Li, Jiarui Li, Jing Li, Jing Li, Bo Yang, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah F. Calubag, Lesley A. Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, Huan Ma
Abstract
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.