A gene called ménage-à-trois 1, or MAT1, plays a crucial role in the function of a master switch for production of energy in the heart cell -- a finding that has important implications for understanding and maybe even treating heart failure, said researchers from Baylor College of Medicine and other institutions in a report published in today's issue of the journal Cell Metabolism.
When Dr. Michael Schneider, professor of medicine, molecular & cellular biology, and molecular physiology & biophysics at BCM, and his colleagues studied infant mice that lacked this gene in their heart muscle cells, "We found that the hearts grew normally. This was surprising, in view of some postulated functions of MAT1. But when the animals reached five weeks of age, they began to succumb to catastrophic heart failure, and all of them were dead by two months."
Using "gene chip" technology, the researchers looked for abnormal patterns of gene expression in hearts from which the MAT1 gene was deleted. They found that genes controlling energy production in cells were particularly affected and that the cells had correspondingly low levels of the proteins required for energy production. The mitochondria -- the cell's energy factories -- were defective.
Further research showed that a particular protein called peroxisome proliferator-activated receptor-1 coactivator, or PGC-1, which is a known master regulator of energy production by cells, did not function in cells that lacked MAT1. Even when the scientists artificially increased the amount of PGC-1 in the cells, its function was decreased if there was no MAT1.
Ultimately, the investigators proved that MAT1 binds to PGC-1 and forms a physical complex with it, providing a direct biochemical explanation for the ability of MAT1 to serve as an essential partner to PGC-1, facilitating its role in regulating cell metabolism.
In fact, two forms of PGC-1 exist -- alpha and beta -- both of which have been reported by other groups to be vital to the heart. Both forms of PGC-1 were shown by Schneider's team to depend highly on MAT1 and to turn on the ordinarily responsive genes for energy production in heart tissue.
"One of the problems in failing hearts is that energy production is deficient," said Schneider. "Drugs that act on the PPARs (peroxisome proliferator activated receptors) and other nuclear receptors to promote better metabolism are a very active area of study. Finding an essential partner of PGC-1 alpha and beta that enables them to switch genes on via these receptors should be helpful in that kind of work."
Others who took part in this investigation include: Drs. Motoaki Sano, Yasukatsu Izumi, Masanori Asakura, Min Xie, George Taffet, Lingyun Hu, Robia G. Pautler, Fernando Scaglia, and Brett H. Graham of Baylor College of Medicine; Katja Helenius, Derrick J. Rossi and Tomi P. Mäkelä of the Molecular Cancer Biolgy Program & Institute of Biomedicine, Biomedicum, Helsinki, Finland; Christopher R. Wilson and Heinrich Taegtmeyer of The University of Texas Health Science Center at Houston; Sihem Boudina and E. Dale Abel of the University of Utah School of Medicine; Anastasia Kralli of The Scripps Research Institute in La Jolla California, and Noriaki Shimizu and Hirotoshi Tanaka of the Institute of Medical Science at the University of Tokyo.
This work was funded by the National Institutes of Health, the Fondation Leducq Translatlantic Network for Excellence for Cardiovascular Research, and the M.D. Anderson Foundation.
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