Study shows PanK2 enzyme within mitochondria is triggered by the first step in fatty acid breakdown

Just as homes have smoke detectors, cells have an enzyme that responds to a buildup of fatty acids by triggering the production of a key molecule in the biochemical pathway that breaks them down, according to investigators at St. Jude Children's Research Hospital. This provides the cell energy while reducing the chance that excess fatty acids will accumulate.

The discovery explains how the fatty acid-sensing enzyme PanK2 tailors production of this key molecule, coenzyme A (CoA), to the cell's energy demands, according to Yong-Mei Zhang, Ph.D., a researcher in the Infectious Diseases department at St. Jude. Understanding PanK2 function is also important because mutations in this enzyme cause PanK-associated neurodegeneration (PKAN), she added. Zhang is senior author of the report that appears in the online pre-publication issue of Proceedings of the National Academy of Sciences.

The team demonstrated that PanK2 responds to increasing levels of fatty acids within mitochondria -- the bags of enzymes in the cell that extract energy from nutrients. The researchers also showed that CoA normally binds tightly to PanK2, shutting it down. When fatty acids accumulate in the cell, a molecule called carnitine shuttles them into the mitochondria. This combination of a fatty acid and carnitine liberates PanK2 from the bondage of CoA. Once free, PanK2 resumes its job of initiating production of more CoA, which is needed for the fatty acid breakdown.

"Our findings suggest that reducing the level of fat in the diet and taking carnitine supplements might help patients with PKAN cope with this debilitating disease," said Roberta Leonardi, Ph.D., a postdoctoral fellow in the Infectious Diseases department at St. Jude and first author of the article.

"We'd like to develop an animal model of this disease to determine whether reduced dietary fat and carnitine supplements offer hope in the treatment of PKAN in humans," said Suzanne Jackowski, Ph.D., a member of the Infectious Diseases department at St. Jude.

The other author is Charles Rock, Ph.D., who is also a member in the Infectious Diseases department of St. Jude.

This work was supported in part by the National Institutes of Health, a Cancer Center (CORE) Support Grant and ALSAC.