Metabolic inflexibility promotes mitochondrial health during liver regeneration

• 成果类型: Article
• 署名作者: Wang, Xun; Menezes, Cameron J.; Jia, Yuemeng; Xiao, Yi; Venigalla, Siva Sai Krishna; Cai, Feng; Hsieh, Meng-Hsiung; Gu, Wen; Du, Liming; Sudderth, Jessica; Kim, Dohun; Shelton, Spencer D.; Llamas, Claire B.; Lin, Yu-Hsuan; Zhu, Min; Merchant, Salma; Bezwada, Divya; Kelekar, Sherwin; Zacharias, Lauren G.; Mathews, Thomas P.; Hoxhaj, Gerta; Wynn, R. Max; Tambar, Uttam K.; Deberardinis, Ralph J.; Zhu, Hao; Mishra, Prashant
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13646
• DOI: 10.1126/science.adj4301
• 发表日期: 2024-06-14
• 关键词: dehydrogenase kinase; partial-hepatectomy; mass-spectrometry; molecular-cloning; fatty liver; homeostasis; resistance; expression; substrate; selection

摘要

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 beta-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.