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
  • 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: [email protected].
  • 11. Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
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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