78b934689483ca0ddb578da82a30ef6a ijms_24_07374.pdf d3c7363b72221e014dd03aea90465edf4b2c429b ijms_24_07374.pdf 1a043b34c297bf9c6adda913d2f5b479a273994401e1a9e99aeb6ca2fcf8fd4b ijms_24_07374.pdf Title: FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells Subject: FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action. Keywords: FTY720-P; mitochondria; TFAM; STAT3; DRP1 S616; cardiomyocytes; metabolism; S1PR; ATP; nucleoids Author: Juan Pablo Muñoz, Paula Sànchez-Fernàndez-de-Landa, Elena María Goretti Diarte-Añazco, Antonio Zorzano, Francisco Blanco-Vaca and Josep Julve Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Apr 17 09:41:36 2023 CEST ModDate: Mon Apr 17 09:56:48 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 8772236 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IXIEZM+VnURWPalladioL Type 1 Custom yes yes no 10 0 FEZEZY+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 ZKKPFU+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 MRYNQF+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 PYPZKK+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 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Children: Item: Title: FTY720-P Increases Mitochondrial Respiration Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: FTY720-P Alters Mitochondrial Morphology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: FTY720-P Increases the Expression of Proteins Involved in Mitochondrial Biogenesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: FTY720-P Increases the Number of Nucleoids Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: STAT3 Signal Was Required to Promote the FTY720-P-Dependent Mitochondrial Metabolism Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Cells and Cell Culture Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Reagents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Antibodies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Western Blotting Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Mitochondrial and Nuclear Enriched Fraction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Immunofluorescence Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Mitochondrial Morphology Analysis and Mitochondrial Nucleoid Quantification Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Mitochondrial Oxygen Consumption Rate (OCR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Measurement of Superoxide, Mitochondrial Potential, and Mitochondrial Membrane Staining Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Oxidation of Metabolic Substrates Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Expression of Results and Statistical Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Info: Title: FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells Author: Juan Pablo Muñoz, Paula Sànchez-Fernàndez-de-Landa, Elena María Goretti Diarte-Añazco, Antonio Zorzano, Francisco Blanco-Vaca and Josep Julve Subject: FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action. 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