β2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis

Abstract

The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB.

Adrenergic control of pinealocyte chondriome – an in vitro study

“…The in vivo administration of clenbuterol, a beta 2 -adrenoceptor agonist, induced prominent ultrastructural changes in mitochondria in the skeletal muscle of mice (Sundal and Sharma 2007). Another agonist of beta 2 -adrenoceptors, formoterol, stimulated mitochondrial biogenesis in cultured adult feline cardiomyocytes (Wills et al 2012) and rabbit renal tubule cells (Wills et al 2012, Peterson et al 2013. Interestingly, isoproterenol and NE were ineffective in these in vitro models (Wills et al 2012, Peterson et al 2013.…”

“…Another agonist of beta 2 -adrenoceptors, formoterol, stimulated mitochondrial biogenesis in cultured adult feline cardiomyocytes (Wills et al 2012) and rabbit renal tubule cells (Wills et al 2012, Peterson et al 2013. Interestingly, isoproterenol and NE were ineffective in these in vitro models (Wills et al 2012, Peterson et al 2013. It has been demonstrated that the betaadrenoceptor pathway enhances mitochondrial function in human neural stem cells (Chiang 2012).…”

“…The role of adrenergic receptors in mitochondrial biogenesis and function has been the subject of many investigations performed on various cell types (Chiang et al 2012, Wills et al 2012, Branco et al 2013, Peterson et al 2013, Pennanen et al 2014. The aim of the present study was to characterize the effect of NE as well as β-and α 1 -adrenergic agonists on mitochondria in pig pinealocytes in organ culture.…”

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

“…Additionally, the reported sirtuin 1 activator SRT-1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo [2,1-b][1,3]thiazol-6-yl] phenyl]quinoxaline-2-carboxamide) promoted MB and expedited recovery of mitochondria following oxidant injury . More recently, b 2 -adrenergic receptor agonists, such as formoterol, were also identified as potent promoters of MB in vitro and in vivo, and a pharmacophore was developed (Wills et al, 2012;Peterson et al, 2013). Interestingly, not all b 2 -adrenoceptor agonists were capable of inducing MB (Peterson et al, 2013).…”

“…More recently, b 2 -adrenergic receptor agonists, such as formoterol, were also identified as potent promoters of MB in vitro and in vivo, and a pharmacophore was developed (Wills et al, 2012;Peterson et al, 2013). Interestingly, not all b 2 -adrenoceptor agonists were capable of inducing MB (Peterson et al, 2013). Finally, specific inhibition of phosphodiesterases 3 and 5 increased cGMP to produce MB in renal proximal tubule cells (RPTC) and mice, and accelerated the recovery of renal function following acute kidney injury (Whitaker et al, 2013).…”