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

Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A. Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, Huan Ma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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-TCmito), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TCnuc). We demonstrated that E-TCmito repurposes molecules traditionally associated with E-TCnuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TCmito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TCmito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.

Original languageEnglish
Article numbereadp6547
JournalScience
Volume386
Issue number6728
DOIs
StatePublished - 20 Dec 2024

Funding

FundersFunder number
Key Project for Hangzhou Medical Disciplines
Project for Hangzhou Medical Disciplines of Excellence
National Institutes of HealthR01MH080047, R35NS116804
National Key Research and Development Program of China2019YFA0508603
National Natural Science Foundation of China31900696, 31722023, 81930030, 82271513, 82230036
Fundamental Research Funds for the Central Universities2024ZFJH01-01, 2023ZFJH01-01
Zhejiang University School of Medicine2021ZD0203501
Chinese Academy of Medical Sciences Initiative for Innovative Medicine2019-I2M-5-057

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