CRI researchers Prashant Mishra, M.D., Ph.D., and Xun Wang, Ph.D.
Researchers have identified a type of metabolic inflexibility during liver regeneration that prevents cells with dysfunctional mitochondria — energy-producing compartments in cells — from proliferating, an important discovery that demonstrates one way regenerative cells root out damage, according to new research from Children’s Medical Center Research Institute at UT Southwestern published in Science.
Prashant Mishra, M.D., Ph.D., Xun Wang, Ph.D., and CRI colleagues found that hepatocytes, the majority of cells forming the liver, normally use their mitochondria to convert fatty acids into acetyl-CoA, a key chemical building block for regeneration. When their mitochondria are damaged, hepatocytes turn on PDK4, a metabolic enzyme that stops the cells from shifting to an alternative source of acetyl-CoA.
“There are good and bad sides of metabolic flexibility. Although metabolic flexibility has been largely proposed as beneficial, our findings suggest that flexibility can also be detrimental by allowing damaged cells to survive,” Mishra said. “In the case of mitochondrial damage, flexibility can be actively suppressed, and this might be a good thing by preventing the damage from spreading.”
Scientists used metabolite profiling and isotope tracing techniques in mice to investigate how mitochondrial health is regulated in wild-type hepatocytes and dysfunctional hepatocytes, both under homeostatic and regenerative conditions. Previous Mishra lab research shows healthy mitochondria are critical for proper organ function and fatty acid metabolism. This newest research shows mitochondrial dysfunction results in livers with excess fat accumulation, which then induces PDK4 and shuts down acetyl-CoA production, ultimately resulting in steatosis, also commonly known as fatty liver disease.
Analyses showed PDK4 expression was a key regulator of metabolic inflexibility. When researchers inhibited PDK4, metabolic flexibility and acetyl-CoA were restored, and the damaged hepatocytes could, again, proliferate.
“Although metabolic flexibility has been largely proposed as beneficial to survival, it’s important to take note that metabolic inflexibility can be used to promote the overall health of regenerating cells,” Mishra said. “Mitochondrial damage is often observed in common human diseases, including fatty liver disease. We hope that by identifying mechanisms cells use to prevent damage from spreading, we can harness these processes to potentially combat disease and prolong health.”
Dr. Mishra is member of CRI’s Genetic and Metabolic Disease Program and collaborated on this research with GMDP Director Ralph DeBerardinis, M.D., Ph.D., and Tissue Regeneration Program Director Hao Zhu, M.D.
Dr. Mishra is an Associate Professor at CRI, leading the Mishra lab, where his team researches how mitochondria are embedded in normal cellular function. His research focuses on how to improve understanding and find new insights into mitochondrial diseases in order to develop clinical tools and therapeutic options. He is also an Associate Professor of Pediatrics at UT Southwestern.
Dr. Wang is a CRI postdoctoral fellow in the Mishra lab.
