Metabolic inflexibility promotes mitochondrial health during liver regeneration

IF 5.6 2区化学 Q1 CHEMISTRY, MEDICINAL

Journal of Chemical Information and Modeling Pub Date : 2024-06-14 DOI:10.1126/science.adj4301

Xun Wang, Cameron J. Menezes, Yuemeng Jia, Yi Xiao, Siva Sai Krishna Venigalla, Feng Cai, Meng-Hsiung Hsieh, Wen Gu, Liming Du, Jessica Sudderth, Dohun Kim, Spencer D. Shelton, Claire B. Llamas, Yu-Hsuan Lin, Min Zhu, Salma Merchant, Divya Bezwada, Sherwin Kelekar, Lauren G. Zacharias, Thomas P. Mathews, Gerta Hoxhaj, R. Max Wynn, Uttam K. Tambar, Ralph J. DeBerardinis, Hao Zhu, Prashant Mishra

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引用次数: 0

Abstract

Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)–dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial β-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.

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新陈代谢不灵活促进肝脏再生过程中的线粒体健康

线粒体对器官的正常功能至关重要，在再生过程中促进线粒体健康的机制将有利于组织的稳态。我们报告说，在肝脏再生过程中，电子传递链（ETC）功能障碍的肝细胞由于无法通过线粒体β-氧化从外周脂肪酸生成乙酰-CoA，增殖受到抑制。在 ETC 功能障碍的情况下，从丙酮酸或乙酸产生乙酰-CoA 的替代模式受到抑制。这种新陈代谢的不灵活性迫使人们对 ETC 功能线粒体产生依赖，而恢复丙酮酸产生乙酰-CoA 就足以让 ETC 功能障碍的肝细胞增殖。我们认为，肝细胞内的新陈代谢不灵活可以限制 ETC 功能失调细胞的增殖，因而是有利的。

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来源期刊

Journal of Chemical Information and Modeling 化学-化学综合

CiteScore

9.80

自引率

10.70%

发文量

529

审稿时长

1.4 months

期刊介绍： The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.