Ikromova Fozila R, Khasanov Feruzbek A, Saidova Malika J, Shokirov Ravshan K, Gazieva Shakhlo, Khadjibaev Abdukhakim M, Tulyaganov Davron B, Akalaev Rustam N, Levitskaya Yulia V, Stopnitskiy Amir A, Baev Artyom Y
Laboratory of Experimental Biophysics, Centre for Advanced Technologies, Tashkent, Uzbekistan.
Department of Biophysics, Faculty of Biology, National University of Uzbekistan, Tashkent, Uzbekistan.
J Bioenerg Biomembr. 2025 Feb;57(1):11-26. doi: 10.1007/s10863-024-10047-6. Epub 2024 Dec 13.
The main therapeutic strategy for the treatment of patients with toxic liver failure is the elimination of the toxic agent in combination with the targeted mitigation of pathological processes that have been initiated due to the toxicant. In the current research we evaluated the strategy of metabolic supplementation to improve mitochondrial bioenergetics during acute liver intoxication. In our study, we have shown that acute CCl-induced intoxication negatively affects Complex I (in the presence of glutamate-malate as energy substrates) based respiration, generation of mitochondrial membrane potential (ΔΨ), mitochondrial NAD(P)H pool and NADH redox index, mitochondrial calcium retention capacity (CRC) and structure and functions of the liver. Boosting of mitochondrial bioenergetics through the complex II, using succinate as metabolic substrate in vitro, significantly improved mitochondrial respiration and generation of ΔΨ, but not mitochondrial CRC. Co-application of rotenone along with succinate, to prevent possible reverse electron flow, didn't show significant differences compared to the effects of succinate alone. Treatment of animals with acute liver failure, using a metabolic supplement containing succinate, inosine, methionine and nicotinamide improved Complex I based respiration, generation of ΔΨ, mitochondrial NAD(P)H pool and NADH redox index, mitochondrial CRC and slightly decreased the level of oxidative stress. These changes resulted in averting destructive and dystrophic changes in the structure of rat liver tissue caused by CCl intoxication, concomitantly enhancing hepatic functionality. Thus, we propose that metabolic supplementation targeting complex II could serve as a potential adjunctive therapy in the management of acute liver intoxication.
治疗中毒性肝衰竭患者的主要治疗策略是消除毒性物质，并针对性地缓解因毒物引发的病理过程。在当前研究中，我们评估了代谢补充策略在急性肝中毒期间改善线粒体生物能量学的效果。在我们的研究中，我们发现急性四氯化碳诱导的中毒会对基于复合体I（以谷氨酸-苹果酸作为能量底物）的呼吸作用、线粒体膜电位（ΔΨ）的产生、线粒体NAD(P)H池和NADH氧化还原指数、线粒体钙保留能力（CRC）以及肝脏的结构和功能产生负面影响。在体外使用琥珀酸作为代谢底物通过复合体II增强线粒体生物能量学，显著改善了线粒体呼吸作用和ΔΨ的产生，但对线粒体CRC没有影响。与单独使用琥珀酸的效果相比，同时应用鱼藤酮和琥珀酸以防止可能的逆向电子流，未显示出显著差异。使用含有琥珀酸、肌苷、蛋氨酸和烟酰胺的代谢补充剂治疗急性肝衰竭动物，改善了基于复合体I的呼吸作用、ΔΨ的产生、线粒体NAD(P)H池和NADH氧化还原指数、线粒体CRC，并略微降低了氧化应激水平。这些变化避免了由四氯化碳中毒引起的大鼠肝组织结构的破坏性和营养不良性变化，同时增强了肝功能。因此，我们提出针对复合体II的代谢补充可能作为急性肝中毒管理中的一种潜在辅助治疗方法。
