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

Our laboratory recently made the novel observation that 5-hydroxytryptamine 1F (5-HT_1F) receptor activation induces mitochondrial biogenesis (MB), the production of new, functional mitochondria, in vitro and in vivo. We sought to determine the mechanism linking the 5-HT_1F receptor to MB in renal proximal tubule cells. Using LY344864, a selective 5-HT_1F receptor agonist, we determined that the 5-HT_1F receptor is coupled to Gα_i/o and induces MB through Gβγ-dependent activation of Akt, endothelial nitric oxide synthase (eNOS), cyclic guanosine-monophosphate (cGMP), protein kinase G (PKG), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). We also report that the 5-HT_1F receptor signals through a second, Gβγ-dependent pathway that is linked by Akt phosphorylation of Raf. In contrast to the activated Akt pathway, Raf phosphorylation reduced extracellular signal regulated kinases (ERK1/2) and foxhead box O3a (FOXO3a) phosphorylation, suppressing an inhibitory MB pathway. These results demonstrate that the 5-HT_1F receptor regulates MB through Gβγ-dependent dual mechanisms that activate a stimulatory MB pathway, Akt/eNOS/cGMP/PKG/PGC-1α, 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.