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Published online before print March 29, 2007 as doi: 10.1096/fj.07-8174com.

Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis

Takeshi Hashimoto, Rajaa Hussien, Saji Oommen, Kishorchandra Gohil, and George A. Brooks

E-mail contact: gbrooks@berkeley.edu

We hypothesized that in addition to serving as a fuel source and gluconeogenic precursor, lactate anion (La-) is a signaling molecule. Therefore, we screened genome-wide responses of L6 cells to elevated (10 and 20 mM) sodium-La- added to buffered, high-glucose media. Lactate increased reactive oxygen species (ROS) production and up-regulated 673 genes, many known to be responsive to ROS and Ca2+. The induction of genes encoding for components of the mitochondrial lactate oxidation complex was confirmed by independent methods (PCR and EMSA). Specifically, lactate increased monocarboxylate transporter-1 (MCT1) mRNA and protein expression within 1 h and cytochrome c oxidase (COX) mRNA and protein expression in 6 h. Increases in COX coincided with increases in peroxisome proliferator activated-receptor {gamma} coactivator-1{alpha} (PGC1{alpha}) expression and the DNA binding activity of nuclear respiratory factor (NRF)-2. We conclude that the lactate signaling cascade involves ROS production and converges on transcription factors affecting mitochondrial biogenesis.--Hashimoto, T., Hussien, R., Oommen, S., Gohil, K., Brooks, G. A. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis.




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