Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury.
Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase β, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-α, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.).
Sara M
SM
Garrett
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.).
Ryan M
RM
Whitaker
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.).
Craig C
CC
Beeson
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.) schnell@musc.edu.
Rick G
RG
Schnellmann
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000032:analysis; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011817:Rabbits; D011985:Receptors, Serotonin / Q000502:physiology*; D015427:Reperfusion Injury / Q000188:drug therapy; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics; D000096642:Receptor, Serotonin, 5-HT1F
D001549:Benzamides; D002227:Carbazoles; D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D005464:Fluorobenzenes; D007211:Indoles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014157:Transcription Factors; D000096642:Receptor, Serotonin, 5-HT1F; C108218:4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide; C109453:LY 344864; C485290:Ppargc1a protein, mouse; C526871:cytochrome c oxidase subunit I, mouse