Pyruvate dehydrogenase complex E1 subunit α crotonylation modulates cocaine-associated memory through hippocampal neuron activation

作者：Hong‐Chun Li, Xiaoyu Liuha, Rong Chen, Yuzhou Xiao, Wei Xu, Yuanyi Zhou, Lin Bai, Jie Zhang, Yue Zhao, Ying Zhao, Liang Wang, Feng Qin, Yaxing Chen, Shuang Han, Qingfan Wei, S. Li, Dingwen Zhang, Qian Bu, Xiaojie Wang, Linhong Jiang, Yanping Dai, Ni Zhang, Weihong Kuang, Meng Qin, Hongbo Wang, Jingwei Tian, Yinglan Zhao, Xiaobo Cen · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.114529 · 被引用次数：9 · 研究领域：Tryptophan and brain disorders、Receptor Mechanisms and Signaling、Neuroscience and Neuropharmacology Research

Neuronal activation is required for the formation of drug-associated memory, which is critical for the development, persistence, and relapse of drug addiction. Nevertheless, the metabolic mechanisms underlying energy production for neuronal activation remain poorly understood. In the study, a large-scale proteomics analysis of lysine crotonylation (Kcr), a type of protein posttranslational modification (PTM), reveals that cocaine promoted protein Kcr in the hippocampal dorsal dentate gyrus (dDG). We find that Kcr is predominantly discovered in a few enzymes critical for mitochondrial energy metabolism; in particular, pyruvate dehydrogenase (PDH) complex E1 subunit α (PDHA1) is crotonylated at the lysine 39 (K39) residue through P300 catalysis. Crotonylated PDHA1 promotes pyruvate metabolism by activating PDH to increase ATP production, thus providing energy for hippocampal neuronal activation and promoting cocaine-associated memory recall. Our findings identify Kcr of PDHA1 as a PTM that promotes pyruvate metabolism to enhance neuronal activity for cocaine-associated memory.