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Protein sensor for fatty acid buildup in mitochondria

February 15, 2007

St. Jude 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 down these fatty acids, according to investigators at St. Jude Children's Research Hospital. This breakdown of fatty acids, in turn, provides the cell energy while reducing the chance that excess fatty acids will accumulate.

The St. Jude discovery explains how the fatty acid-sensing enzyme PanK2 tailors production of this key molecule, coenzyme A (CoA), to the cell's energy demands. Understanding PanK2 function is also important because mutations in this enzyme cause an inherited neurodegenerative disease. A report on the discovery appears in the online pre-publication issue of Proceedings of the National Academy of Sciences (PNAS).

"The results of this study show how and where a critical biochemical pathway for fatty acid breakdown is controlled by a specific enzyme," said Charles Rock, Ph.D., a member of the Infectious Diseases department at St. Jude. "It offers an explanation of why the absence of this enzyme can cause mitochondrial malfunction." Rock is a co-author of the PNAS paper.

The researchers showed that PanK2, is suppressed by CoA—the molecule this enzyme triggers the cell to make. CoA normally binds tightly to PanK2, shutting it down. When a buildup of fatty acids occurs in the cell, a molecule called carnitine shuttles them into the mitochondria. This combination of a fatty acid and carnitine, called acylcarnitine, liberates PanK2 from the bondage of CoA. Once free, PanK2 resumes its job of initiating the production of more CoA, which is needed for the breakdown of fatty acids—a process called beta-oxidation.

The St. Jude team demonstrated that PanK2 does its job of responding to increasing levels of fatty acids within a structure called the mitochondrion. Mitochondria are bags of enzymes in the cell that extract energy from nutrients. Most of the cell's energy-rich molecules called ATP are made in the mitochondria, and these ATP molecules serve as the "currency" with which the cell can "buy" all of the biochemical reactions that keep the cell alive and performing its functions. Virtually all cells have mitochondria, and disruption of their function can cause a variety of diseases.

"Our study showed the connection between the location of PanK2 in the mitochondria and its role in as a sensor of energy demand," said Yong-Mei Zhang, Ph.D., a researcher in the Infectious Diseases department at St. Jude and the report's senior author. "This is an ideal location for PanK2 because it can detect acylcarnitine as it enters the mitochondrion."

The importance of PanK2 is especially evident in individuals who have mutations in the PANK2 gene that give rise to PanK-associated neurodegeneration (PKAN), an inherited disease in which patients have intellectual impairment and difficulty in walking and speaking.

"The new understanding of PanK2 activity and its location in the cell suggests a potential treatment strategy for PKAN," said Roberta Leonardi, Ph.D., a postdoctoral fellow in the St. Jude Infectious Diseases department and first author of the PNAS article. "For example, reducing the level of fat in the diet and taking carnitine supplements might help PKAN patients cope with this debilitating disease."

"One of our challenges is how to develop an animal model of this disease that we can use to determine if 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 and a co-author of the report.

St. Jude Children's Research Hospital