Abstract |
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.
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Authors | Sara M Garrett, Ryan M Whitaker, Craig C Beeson, Rick G Schnellmann |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 350
Issue 2
Pg. 257-64
(Aug 2014)
ISSN: 1521-0103 [Electronic] United States |
PMID | 24849926
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | U.S. Government work not protected by U.S. copyright. |
Chemical References |
- 4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide
- Benzamides
- Carbazoles
- DNA, Mitochondrial
- Fluorobenzenes
- Indoles
- LY 344864
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Ppargc1a protein, mouse
- Receptors, Serotonin
- Serotonin Receptor Agonists
- Transcription Factors
- serotonin 1F receptor
- Electron Transport Complex IV
- cytochrome c oxidase subunit I, mouse
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Topics |
- Acute Kidney Injury
(drug therapy, physiopathology)
- Animals
- Benzamides
(pharmacology)
- Carbazoles
(pharmacology)
- DNA, Mitochondrial
(analysis)
- Electron Transport Complex IV
(genetics)
- Female
- Fluorobenzenes
(pharmacology)
- Indoles
(pharmacology)
- Kidney
(drug effects, metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria
(drug effects, physiology)
- Oxidative Phosphorylation
(drug effects)
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Rabbits
- Receptors, Serotonin
(physiology)
- Reperfusion Injury
(drug therapy)
- Serotonin Receptor Agonists
(pharmacology)
- Transcription Factors
(genetics)
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