Lithium increases PGC-1alpha expression and mitochondrial biogenesis in primary bovine aortic endothelial cells.
Lithium is a therapeutic agent commonly used to treat bipolar disorder and its beneficial effects are thought to be due to a combination of activation of the Wnt/beta-catenin pathway via inhibition of glycogen synthase kinase-3beta and depletion of the inositol pool via inhibition of the inositol monophosphatase-1. We demonstrated that lithium in primary endothelial cells induced an increase in mitochondrial mass leading to an increase in ATP production without any significant change in mitochondrial efficiency. This increase in mitochondrial mass was associated with an increase in the mRNA levels of mitochondrial biogenesis transcription factors: nuclear respiratory factor-1 and -2beta, as well as mitochondrial transcription factors A and B2, which lead to the coordinated upregulation of oxidative phosphorylation components encoded by either the nuclear or mitochondrial genome. These effects of lithium on mitochondrial biogenesis were independent of the inhibition of glycogen synthase kinase-3beta and independent of inositol depletion. Also, expression of the coactivator PGC-1alpha was increased, whereas expression of the coactivator PRC was not affected. Lithium treatment rapidly induced a decrease in activating Akt-Ser473 phosphorylation and inhibitory Forkhead box class O (FOXO1)-Thr24 phosphorylation, as well as an increase in activating c-AMP responsive element binding (CREB)-Ser133 phosphorylation, two mechanisms known to control PGC-1alpha expression. Together, our results show that lithium induces mitochondrial biogenesis via CREB/PGC-1alpha and FOXO1/PGC-1alpha cascades, which highlight the pleiotropic effects of lithium and reveal also novel beneficial effects via preservation of mitochondrial functions.
Struewing
Ian T
IT
Graduate Center for Nutritional Sciences, University of Kentucky, 900 Limestone Street, Lexington, KY 40536, USA.
Barnett
Corey D
CD
Tang
Tao
T
Mao
Catherine D
CD
D000818:Animals; D002417:Cattle; D048429:Cell Size / Q000187:drug effects; D045303:Cytochromes b / Q000096:biosynthesis; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000096:biosynthesis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis*
D021122:Protein Subunits; D015534:Trans-Activators; D045303:Cytochromes b; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C412204:ATP synthase subunit 6; D025261:Mitochondrial Proton-Translocating ATPases; D018021:Lithium Chloride