The central nervous system (CNS) and the immune system might cooperate with each other on various levels in a body. Interestingly, signaling pathways linked to several G protein-coupled receptors (GPCRs) have been shown to be involved in the pathology both of CNS disorders including neurodegenerative diseases and/or immune-related diseases. Oxidative stress and inflammation are likely to contribute to cell damage and death in these disorders, which in turn could cause mitochondrial injury. Interestingly, it has been revealed that gut microbiota could play a significant role in changing the phenotype of various neuron and/or immune-related disorders. Remarkably, GPCR signaling has been recognized as a key upstream regulator for autophagy/mitophagy via the action of the mammalian/mechanistic target of rapamycin (mTOR) signaling. In addition, adjusting the composition of gut microbiota could be applied to modulate the autophagy/mitophagy by the alteration of GPCR signaling to ameliorate the mitochondrial injury. Collectively, this approach may contribute to the innovative development of promising therapeutics for neurodegenerative diseases and/or immune-related diseases. This review describes that concept, highlighting the intracellular mTOR signaling from the cell surface GPCRs within cells of Gut-brain-immune axis.