A strong link between the SHANK3 gene mutations and autism spectrum disorder (ASD) has been established but its molecular mechanisms remain unknown. Here we hypothesize that a mutation in the Shank3 gene leads to alterations in the global proteome, and consequently, these alterations converge into cellular and behavioral deficits of ASD. To test this hypothesis, we comprehensively mapped the global proteome within the cortex of the Shank3Δ4-22 mice. Our preliminary results revealed a significant increase in one of the ATP synthase subunits (ATP-S) expression levels in the cortex of Shank3Δ4-22 mice compared to their wild-type counterparts. Previous studies have indicated that mitochondrial dysfunction plays a role in the pathophysiology of ASD. Consistently, our findings suggest that upregulation of this subunit leads to mitochondrial dysfunction, which in turn contributes to synaptic and behavioral deficits. Thus, we first aim to examine the mitochondrial dysfunction results from the upregulation of ATP-S. Hence, we measured the mitochondrial respiration on Shank3Δ422 cortical neurons. Notably, our findings revealed a significant increase in mitochondrial proton leak which subsequently contributed to the impairment of mitochondrial membrane potential. Following that we plan to block the ATP-S leak using HU-55 molecule and test the molecular, synaptic, and behavioral phenotypes. Our preliminary data showed that following the administration of HU-55 to Shank3Δ4-22 mice, we observed a partial reversal of the autistic phenotype. Collectively, this study may provide a structured framework to comprehensively explore the complex interplay between protein expression, mitochondrial function, and potential therapeutic interventions for ASD.