Li Wenwen, Li Jiarui, Li Jing, Wei Chen, Laviv Tal, Dong Meiyi, Lin Jingran, Calubag Mariah, Colgan Lesley A, Jin Kai, Zhou Bing, Shen Ying, Li Haohong, Cui Yihui, Gao Zhihua, Li Tao, Hu Hailan, Yasuda Ryohei, Ma Huan
Department of Neurology of Second Affiliated Hospital and Liangzhu Laboratory, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Affiliated Mental Health Center and Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Science. 2024 Dec 20;386(6728):eadp6547. doi: 10.1126/science.adp6547.
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), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TC). We demonstrated that E-TC repurposes molecules traditionally associated with E-TC to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TC weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TC in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.
破解神经元活动与线粒体功能之间复杂的相互作用对于理解大脑衰老至关重要，大脑衰老是一个多方面的过程，其特征是突触功能和线粒体性能下降。在这里，我们发现了神经元与突触兴奋和线粒体DNA转录（E-TC）之间的年龄依赖性耦合，它与细胞核中的经典兴奋-转录耦合（E-TC）的运作方式不同。我们证明，E-TC重新利用传统上与E-TC相关的分子来调节与突触激活密切相关区域的线粒体DNA表达。E-TC的有效性随着年龄的增长而减弱，导致小鼠出现与年龄相关的神经缺陷。提高老年动物大脑中的E-TC可改善这些损伤，为对抗与年龄相关的认知衰退提供了一个潜在靶点。
