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

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

  • Cell Metab. 2025 Oct 7;37(10):2076-2092.e8. doi: 10.1016/j.cmet.2025.08.003.
Panpan Xian 1,  Mengmeng Wang 2,  Rougang Xie 2,  Hongyu Ma 3,  Weian Zheng 2,  Junjun Kang 2,  Yujiang Chen 4,  Hanze Liu 5,  Songqi Dong 2,  Haiying Liu 2,  Wenle Zhang 6,  Honghui Mao 2,  Fang Wang 7,  Ning Yang 7,  Jun Yu 8,  Ningxia Zhao 9,  Yazhou Wang 10,  Shengxi Wu 11
Affiliations

Affiliations

  • 1 Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
  • 2 Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 3 Department of Neurobiology, Hebei Medical University, Shijiazhuang, Hebei 050000, China.
  • 4 Department of Pediatric Dentistry, State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 5 Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Neurobiology, Medical College of Yan'an University, Yan'an 716000, China.
  • 6 Analysis and Testing Laboratory for Life Sciences and Medicine of Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 7 Pediatric Rehabilitation Department of Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710032, China.
  • 8 Clinical Experimental Center, The Affiliated Xi'an International Medical Center Hospital, Northwest University, Xi'an, Shaanxi 710100, China.
  • 9 Xi'an TCM Hospital of Encephalopathy, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 710032, China.
  • 10 Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: yazhouw@fmmu.edu.cn.
  • 11 Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: shengxi@fmmu.edu.cn.
PMID: 40907489 DOI: 10.1016/j.cmet.2025.08.003
Abstract

Clinical studies have identified 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.

Keywords

H(2)S; autism spectrum disorder; mGluR5; social dysfunction; sulfhydration.

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