Decoding the Bile Acid-Mitochondria Axis: Implications for Disease Management and Therapeutic Opportunities

Bile acids, as cholesterol metabolites, orchestrate a regulatory network with mitochondrial quality control (MQC) through nuclear receptor FXR, membrane receptor TGR5, and other signaling molecules, modulating mitochondrial biogenesis, dynamic equilibrium, selective autophagy, and redox homeostasis. TGR5 promotes PGC-1α-mediated mitochondrial biogenesis via the cAMP-PKA-CREB pathway, while concurrently regulating mitochondrial fission and calcium homeostasis through the PKCδ/Drp1 and GRP75-MAMs pathways. FXR, acting through transcriptional reprogramming and epigenetic mechanisms, governs fatty acid oxidation, antioxidant defense, and apoptotic pathways, and has been shown to restore PINK1/Parkin-dependent autophagy and suppress NLRP3 inflammasome activation in alcoholic liver disease. Noncanonical receptors, including S1PR2, VDR, and PXR, also participate in the regulation of mitochondrial dynamics and autophagy. Dysregulation of this network is closely associated with metabolic dysfunction-associated fatty liver disease, diabetic retinopathy, pancreatic β-cells injury, alcoholic liver disease, and sepsis-induced immunoparalysis. Agonists targeting the aforementioned receptors, such as INT-777, INT-767, and Fexaramine, have demonstrated the capacity to restore mitochondrial function and alleviate tissue damage in animal models. Future investigations should employ multi-omics and structural biology approaches to elucidate receptor crosstalk and concentration-dependent bidirectional effects, and to develop tissue-selective modulators, thereby facilitating clinical translation.