5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis.
Rasbach K, Funk JA, Jayavelu T, Green PT, Schnellmann RG.
J Pharmacol Exp Ther. 2009 Oct 29. [Epub ahead of print]
Medical University of South Carolina.
Medical University of South Carolina.
Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug and toxicant injury. Following injury renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, PGC-1alpha. The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. RT-PCR analysis confirmed the presence of 5-HT2A, 5-HT2B and 5-HT2C receptor mRNA in RPTC. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) (3-10 muM) increased PGC-1alpha levels, expression of mitochondrial proteins ATP synthase beta and NDUFB8, MitoTracker Red staining intensity, cellular respiration and ATP levels through a 5-HT receptor and PGC-1alpha dependent pathway. Similar effects were observed with the 5-HT2 agonist m-chlorophenylpiperazine (mCCP) and were blocked by the 5-HT2 antagonist 8-[3-(4-fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193). Additionally, DOI accelerated the recovery of mitochondrial function following oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor mediated mitochondrial biogenesis and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury.
PMID: 19875674 [PubMed - as supplied by publisher]
