Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis.
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-1alpha (PGC1alpha) 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
Takeshi
T
Department of Integrative Biology, University of California, Berkeley, CA 94720-3140 USA.
Hussien
Rajaa
R
Oommen
Saji
S
Gohil
Kishorchandra
K
Brooks
George A
GA
D000818:Animals; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D024202:Electrophoretic Mobility Shift Assay; D005947:Glucose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007739:L Cells; D007773:Lactates / Q000378:metabolism*; D051379:Mice; D008931:Mitochondria, Muscle / Q000502:physiology*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D027981:Symporters / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
D004247:DNA; D005947:Glucose; D006861:Hydrogen Peroxide; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D014157:Transcription Factors; D000099233:Monocarboxylate Transport Protein 1