Metabolic inflexibility promotes mitochondrial health during liver regeneration
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, Richard Wynn, Uttam K. Tambar, Ralph J. DeBerardinis, Hao Zhu, Prashant Mishra
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.