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

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.