AUTHOR=Brose Stephen A. , Golovko Svetlana A. , Golovko Mikhail Y. 

TITLE=Fatty Acid Biosynthesis Inhibition Increases Reduction Potential in Neuronal Cells under Hypoxia

JOURNAL=Frontiers in Neuroscience

VOLUME=10

YEAR=2016

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2016.00546

DOI=10.3389/fnins.2016.00546

ISSN=1662-453X

ABSTRACT=<p>Recently, we have reported a novel neuronal specific pathway for adaptation to hypoxia through increased fatty acid (FA) biosynthesis followed by esterification into lipids. However, the biological role of this pathway under hypoxia remains to be elucidated. In the presented study, we have tested our hypothesis that activation of FA synthesis maintains reduction potential and reduces lactoacidosis in neuronal cells under hypoxia. To address this hypothesis, we measured the effect of FA synthesis inhibition on <inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msubsup><mml:mtext>NADH</mml:mtext><mml:mn>2</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:mrow></mml:math></inline-formula>/NAD<sup>+</sup> and <inline-formula><mml:math id="M2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msubsup><mml:mtext>NADPH</mml:mtext><mml:mn>2</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:mrow></mml:math></inline-formula>/NADP<sup>+</sup> ratios, and lactic acid levels in neuronal SH-SY5Y cells exposed to normoxic and hypoxic conditions. FA synthesis inhibitors, TOFA (inhibits Acetyl-CoA carboxylase) and cerulenin (inhibits FA synthase), increased <inline-formula><mml:math id="M3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msubsup><mml:mtext>NADH</mml:mtext><mml:mn>2</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:mrow></mml:math></inline-formula>/NAD<sup>+</sup> and <inline-formula><mml:math id="M4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msubsup><mml:mtext>NADPH</mml:mtext><mml:mn>2</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:mrow></mml:math></inline-formula>/NADP<sup>+</sup> ratios under hypoxia. Further, FA synthesis inhibition increased lactic acid under both normoxic and hypoxic conditions, and caused cytotoxicity under hypoxia but not normoxia. These results indicate that FA may serve as hydrogen acceptors under hypoxia, thus supporting oxidation reactions including anaerobic glycolysis. These findings may help to identify a radically different approach to attenuate hypoxia related pathophysiology in the nervous system including stroke.</p>