5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

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, peroxisomeproliferator-activated-receptor-␥-coactivator-1␣ (PGC-1␣). 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. -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.

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

“…Activators of silent mating type information regulation 2 homolog 1 (SIRT1)-including isoflavones, resveratrol, and N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide (SRT1720) -have been demonstrated to induce PGC-1a and promote increased mitochondrial number and function (Rasbach and Schnellmann, 2008;Funk et al, 2010;Menzies et al, 2013). Our laboratory also identified the 5-hydroxytryptamine type 2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), and the b 2 -adrenergic receptor agonist, formoterol, as potent inducers of PGC-1a and MB (Rasbach et al, 2010;Wills et al, 2012). Stimulation of MB after injury accelerates recovery of cellular morphology and function (Rasbach and Schnellmann, 2007;Funk et al, 2010;Rasbach et al, 2010).…”

5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists

“…An early examination of the effects of a 5-HT 2 pan-agonist, DOI, revealed that it induced MB and promoted recovery of cellular respiration in RPTCs after acute oxidant injury (Rasbach et al, 2010). In this study, we sought to further define the role of the 5-HT 2 receptors in renal mitochondrial gene expression and oxidative metabolism.…”

“…Primer sequences for 5-HT 2A , 5-HT 2B , and 5-HT 2C were previously described (Rasbach et al, 2010).…”

“…Our drug discovery program in MB has previously identified several pharmacological targets that activate PGC-1a and induce MB, including the b 2 adrenergic receptor, phosphodiesterases inhibitors, and the 5-HT 2 class of receptors (Rasbach et al, 2010;Wills et al, 2012). Of these targets, the role of the 5-HT 2 receptor in mitochondrial signaling has been explored the least.…”

“…Consequently, previous investigations into the role of the renal 5-HT 2 receptor in mitochondria demonstrated that DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine], a nonselective 5-HT 2 receptor agonist, induced MB and repaired mitochondrial dysfunction caused by acute oxidant injury in RPTCs (Rasbach et al, 2010). However, because DOI is a 5-HT 2 receptor pan-agonist, the MB activity could not be assigned to a specific 5-HT 2 receptor.…”