CRI Associate Professor Prashant Mishra, M.D., Ph.D., Xun Wang, Ph.D., and colleagues have found that hepatocytes, the cells responsible for most liver function, normally use their mitochondria to process fatty acids, a key energy source during regeneration. When their mitochondria are damaged, hepatocytes turn on PDK4 – a metabolic enzyme that restricts cells from shifting to an alternative energy source – and cells die.

“There are good and bad sides of metabolic flexibility. Although metabolic flexibility has been largely described as beneficial because it gives cells the ability to tolerate shifting environments or alternative nutritional sources, our findings suggest flexibility can also be detrimental by allowing damaged cells to survive,” Dr. Mishra said. “With mitochondrial damage, liver cells actively suppress flexibility – a good thing if it prevents the damage from spreading.”

CRI scientists initially studied the mitochondria of healthy liver cells, both under normal and regenerative conditions. Their analyses showed fatty acids from other parts of the body were transported through the blood to the liver to fuel regeneration. When researchers blocked fatty acid transit, heathy livers were flexible and shifted to other energy sources, including sugars like glucose.

Researchers then examined livers from mice with mutations in their mitochondrial genes. Damaged liver cells were unable to use fatty acids during regeneration and did not shift to other energy sources, preventing livers from regenerating.

To understand why the flexibility was suppressed by mitochondrial mutations, Mishra Lab members examined genes that control a cell’s ability to use alternate energy sources. Results showed increased levels of the PDK4 gene – a negative regulator of a pathway needed to generate energy from glucose. When researchers blocked PDK4, damaged cells in the liver became metabolically flexible and were able to use other energy sources to spread and duplicate.