Pavlova Evgeniya K, Samartsev Victor N, Dubinin Mikhail V
Mari State University, pl. Lenina 1, Yoshkar-Ola, Mari El, 424001, Russia.
J Bioenerg Biomembr. 2025 Feb;57(1):39-48. doi: 10.1007/s10863-024-10048-5. Epub 2024 Dec 19.
Cholestasis caused by impaired bile secretion in the liver is associated with the accumulation of primary bile acids (BA): cholic acid (CA) and chenodeoxycholic acid (CDCA) in the cells of this organ. The paper studies the uncoupling effect of the CA and CDCA on the succinate-fueled rat liver mitochondria under conditions of ΔpH to Δψ conversion by nigericin. It has been established that without nigericin, the dependence of the resting-state (state 4) respiration rate on the concentrations of these BA is nonlinear and is described by a parabolic equation. Under these conditions, the specific inhibitor of the ADP/ATP-antiporter - carboxyatractylate and the substrate of the aspartate/glutamate-antiporter - glutamate do not affect the state 4 respiration of mitochondria stimulated by these BA. It is suggested that without nigericin, the protonophore action of BA is due to the formation of a dimeric complex of their anion with the acid. In the presence of nigericin, the dependence of state 4 respiration rate on BA concentration is linear. Under these conditions, carboxyatractylate inhibits BA-stimulated respiration. Unlike the CDCA, the uncoupling action of CA is also suppressed by the substrates of the aspartate/glutamate-antiporter. The obtained results are considered as evidence that in the presence of nigericin, uncoupling action of CDCA is carried out primarily with the participation of ADP/ATP-antiporter. Both ADP/ATP-antiporter and aspartate/glutamate-antiporter are involved in the uncoupling action of CA. It is concluded that nigericin modifies the mechanism of the uncoupling action of BA in liver mitochondria by converting ΔpH to Δψ.
肝脏中胆汁分泌受损引起的胆汁淤积与该器官细胞中初级胆汁酸（BA）的积累有关：胆酸（CA）和鹅去氧胆酸（CDCA）。本文研究了在尼日利亚菌素将ΔpH转化为Δψ的条件下，CA和CDCA对琥珀酸供能的大鼠肝脏线粒体的解偶联作用。已经确定，在没有尼日利亚菌素的情况下，静息状态（状态4）呼吸速率对这些BA浓度的依赖性是非线性的，可用抛物线方程描述。在这些条件下，ADP/ATP反向转运体的特异性抑制剂——羧基苍术苷和天冬氨酸/谷氨酸反向转运体的底物——谷氨酸不会影响这些BA刺激的线粒体状态4呼吸。有人认为，在没有尼日利亚菌素的情况下，BA的质子载体作用是由于其阴离子与酸形成了二聚体复合物。在存在尼日利亚菌素的情况下，状态4呼吸速率对BA浓度的依赖性是线性的。在这些条件下，羧基苍术苷抑制BA刺激的呼吸。与CDCA不同，CA的解偶联作用也受到天冬氨酸/谷氨酸反向转运体底物的抑制。所获得的结果被认为是证据，表明在存在尼日利亚菌素的情况下，CDCA的解偶联作用主要通过ADP/ATP反向转运体参与进行。ADP/ATP反向转运体和天冬氨酸/谷氨酸反向转运体都参与了CA的解偶联作用。得出的结论是，尼日利亚菌素通过将ΔpH转化为Δψ来改变肝脏线粒体中BA解偶联作用的机制。
