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Protein sensor for fatty acid buildup in mitochondria

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 nutrie
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Source:St. Jude Children's Research Hospital


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