Bile acids, as end products of cholesterol metabolism, participate in a regulatory network that directly interacts with mitochondrial quality control (MQC) systems. This network influences core MQC processes including mitochondrial biogenesis, the balance of mitochondrial fusion and fission (dynamic equilibrium), selective autophagy of mitochondria (mitophagy), and maintenance of redox homeostasis. These effects are mediated through multiple bile acid receptors and downstream signaling pathways described in the source review.
The membrane G protein–coupled receptor TGR5 promotes mitochondrial biogenesis through activation of PGC‑1α via the cAMP–PKA–CREB signaling cascade. In addition to stimulating biogenesis, TGR5 signaling influences mitochondrial fission and intracellular calcium balance. These latter effects are mediated, at least in part, by the PKCδ/Drp1 axis (linking to fission machinery) and by GRP75–MAMs (the mitochondria–associated membranes that govern ER–mitochondria calcium exchange). Collectively, these TGR5‑dependent pathways coordinate the production of new mitochondria with the dynamic remodeling and calcium handling necessary for cellular metabolic adaptation.
The nuclear receptor FXR exerts control over mitochondrial function primarily through transcriptional reprogramming and epigenetic mechanisms. FXR influences genes involved in fatty acid oxidation, antioxidant defenses, and apoptotic pathways, thereby shaping mitochondrial metabolic competence and stress responses. In disease models of alcoholic liver disease, FXR activation has been reported to restore PINK1/Parkin‑dependent mitophagy and to suppress activation of the NLRP3 inflammasome, linking FXR signaling to both mitochondrial quality control and inflammatory regulation.
Beyond FXR and TGR5, the review identifies several noncanonical bile acid receptors that contribute to mitochondrial regulation. These include S1PR2, the vitamin D receptor (VDR), and the pregnane X receptor (PXR). Each of these receptors participates in pathways that affect mitochondrial dynamics and autophagy, extending the complexity of the bile acid–mitochondria axis and suggesting multiple nodes for potential modulation.
The authors link dysregulation of the bile acid–mitochondria network to a range of pathologies across metabolic, endocrine, ophthalmic, hepatic, and immune domains. Specific conditions cited in the review are metabolic dysfunction‑associated fatty liver disease (MAFLD), diabetic retinopathy, pancreatic β‑cell injury, alcoholic liver disease, and sepsis‑induced immunoparalysis. In these contexts, disturbed bile acid signaling is associated with impaired mitochondrial quality control, which may contribute to disease progression and tissue injury.
Several receptor‑targeting small molecules are noted for their capacity to restore mitochondrial function and ameliorate tissue damage in animal models. Examples explicitly mentioned in the review include the TGR5 or bile acid receptor agonists INT‑777, INT‑767, and the FXR agonist Fexaramine. According to the source abstract, these compounds have demonstrated efficacy in preclinical studies, supporting the translational potential of receptor‑directed modulation of the bile acid–mitochondria axis. The abstract does not provide specific experimental details or clinical trial data.
The authors call for advanced experimental approaches to resolve remaining knowledge gaps. Specifically, they recommend application of multi‑omics techniques and structural biology to elucidate receptor crosstalk and the mechanisms of concentration‑dependent, bidirectional effects of bile acids on mitochondrial pathways. They also emphasize the need to develop tissue‑selective modulators of bile acid receptors to improve therapeutic specificity and facilitate movement from preclinical models toward clinical translation. Details on experimental design, dosing, or timelines were not reported in the abstract.
Overall, the review synthesizes evidence that bile acids function as key regulators of mitochondrial quality control through multiple receptors and signaling axes. This bile acid–mitochondria interplay is implicated in several clinically relevant disease states, and receptor‑targeted agonists have shown promise in animal models. The authors propose focused mechanistic and translational research to clarify receptor interactions and to create tissue‑selective therapeutics for human disease.