{5-Hydroxytryptamine} Receptor Stimulation of Mitochondrial Biogenesis

  • Rasbach K
  • Funk J
  • Jayavelu T
 et al. 
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Abstract

Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells {(RPTC)} recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisome-proliferator-activated-receptor-γ-coactivator-1α {(PGC-1α).} 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. Reverse transcription-polymerase chain reaction 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 {μM)} increased {PGC-1α} levels, expression of mitochondrial proteins {ATP} synthase β and {NADH} dehydrogenase (ubiquinone) 1β subcomplex 8 {(NDUFB8),} {MitoTracker} Red staining intensity, cellular respiration, and {ATP} levels through a {5-HT} receptor and {PGC-1α-dependent} pathway. Similar effects were observed with the {5-HT2} agonist m-chlorophenylpiperazine 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).} In addition, {DOI} accelerated the recovery of mitochondrial function after 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.

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Authors

  • Kyle Rasbach

  • Jason Funk

  • Tamilselvan Jayavelu

  • Peter Green

  • Rick Schnellmann

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