Identification of dual mechanisms mediating 5-hydroxytryptamine receptor 1F-induced mitochondrial biogenesis

laboratory recently made the novel observation that 5-hydroxytryptamine 1F (5-11T(IF)) receptor activation induces mitochondria' biogenesis (MB), the production of new, functional mitochondria, in vitro and in vivo. We sought to determine the mechanism linking the 5-HTIF receptor to MB in renal proximal tubule cells. Using LY344864, a selective 5-HT1F flip receptor agonist, we determined that the 5-HT1F receptor is coupled to Guik, and induces MB through G beta gamma-dependent activation of Akt, endothelial nitric oxide synthase (eNOS), cyclic guanosine-monophosphate (cGMP), protein kinase G (PKG), and peroxisome proliferator-activated receptor-gamma coactivator-gamma (PGC-l alpha). We also report that the 5-HT1F, receptor signals through a second, (G beta gamma-dependent pathway that is linked by Akt phosphorylation of Raf. In contrast to the activated Akt pathway, Raf phosphorylation reduced extracellular signal regulated kinases (ERKI/2) and foxhead box 03a (FOX03a) phosphorylation, suppressing an inhibitory MB pathway. These results demonstrate that the 5-HT1F receptor regulates MB through G beta gamma-dependent dual mechanisms that activate a stimulatory MB pathway, Akt/eNOS/cGMP/PKG/PGC-1 alpha, while simultaneously repressing an inhibitory MB pathway, Raf/MEK/ERK/FOXO3a. Novel mechanisms of MB provide the foundation for new chemicals that induce MB to treat acute and chronic organ injuries.