第四军医大学武胜昔团队宣布他们揭示了线粒体功能障碍揭示H2S介导的突触巯基化是自闭症相关社会缺陷的潜在机制。2025年9月3日出版的《细胞—代谢》杂志发表了这项成果。

在这项研究中，该课题组人员聚焦于前扣带皮层（ACC），并报道了硫化氢（H₂S）升高是Shank3b^-/-线粒体功能障碍的常见结果。和Fmr1^-/y神经元。ACC中胱胱硫氨酸β合酶的过表达会损害野生型小鼠的突触传递和社交功能，而其敲低则有效地挽救了两种自闭症母型小鼠的突触和社交缺陷。突触蛋白巯基化在Shank3b^-/-/ACC， mGluR5过巯基化在两种模型中都得到了验证。消融mGluR5巯基化可以部分缓解两种菌株的社会缺陷。

此外，硫氨基酸限制改善了Shank3b^-/-和Fmr1^-/y小鼠和相应的人类神经元突触缺陷。他们的数据表明，过量的H₂S和突触蛋白巯基化可能是自闭症相关社交功能障碍的潜在机制。

据介绍，临床研究已经证实自闭症患者外周组织中的多种线粒体紊乱。然而，神经元代谢如何促成自闭症相关表型仍不清楚。

附：英文原文

Title: Mitochondrial dysfunction reveals H2S-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects

Author: Panpan Xian, Mengmeng Wang, Rougang Xie, Hongyu Ma, Weian Zheng, Junjun Kang, Yujiang Chen, Hanze Liu, Songqi Dong, Haiying Liu, Wenle Zhang, Honghui Mao, Fang Wang, Ning Yang, Jun Yu, Ningxia Zhao, Yazhou Wang, Shengxi Wu

Issue&Volume: 2025-09-03

Abstract: Clinical studies have identied multiple mitochondrial disturbances in the peripheral tissues of patients with autism. However, how neuronal metabolism contributes to the autism-associated phenotype remains unclear. In this study, we focused on the anterior cingulate cortex (ACC) and reported hydrogen sulfide (H2S) elevation as a common outcome to mitochondrial dysfunction in Shank3b/ and Fmr1/y neurons. Cystathionine β-synthase overexpression in ACC impaired synaptic transmission and social function in wild-type mice, while its knockdown effectively rescued synaptic and social defects in both autism mouse models. Dramatic changes in synaptic protein sulfhydration were observed in Shank3b/ ACC, with over-sulfhydration of mGluR5 validated in both models. Ablating mGluR5 sulfhydration partially alleviated social deficits in both strains. Furthermore, sulfur amino acid restriction ameliorated social dysfunction in Shank3b/ and Fmr1/y mice and synaptic defects in corresponding human neurons. Our data indicate that excessive H2S and synaptic protein sulfhydration may serve as potential mechanisms underlying the autism-associated social dysfunction.

DOI: 10.1016/j.cmet.2025.08.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00359-6