Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.

Keywords: S-nitrosylation; autism spectrum disorder; nitric oxide; proteomics mitochondria; systems biology.

Figure 1

System biology analysis of the S-nitroso-proteome in the ASD mouse model. (A) BP, (B) MF, and (C) CC analyses were conducted on the SNO proteins. Bars represent the −log10 of the Benjamini-corrected false discovery rate (FDR). (D) Network analysis was conducted on the mitochondrial SNO proteins (n = 63).

Figure 2

Schematic figure showing the respiratory electron transport chain (ETC) that drives the ATP synthesis. Electrons from NADH are transferred to oxygen by a series of unique and large protein complexes (I-IV) in the inner mitochondrial membrane, which creates the electrochemical gradient required for ATP synthesis by ATP5A1. ATP5A1: mitochondrial ATP synthase produces ATP from ADP in the presence of a proton gradient generated by the ETC. S-nitrosylation of ATP5A1 inhibits its activity. VDAC2: voltage-dependent anion-selective channel protein 2. S-nitrosylation of VDAC2 increases its activity. ROS: Reactive oxygen species, a byproduct of the ETC.