Irisin regulates mitochondrial function to support synaptogenesis in the developing hippocampus

Hippocampal synapse proliferation is a critical period in brain development that demands vast supplies of chemical energy. Maternally derived hormones exert vital effects on mitochondrial function in the developing brain, thus determining neuronal synapse proliferative capacity. Here we investigated the mechanisms by which irisin, through the neuronal uncoupling proteins (UCPs) UCP2, UCP4, and UCP5, regulates mitochondrial function to facilitate the growth and maturation of dendritic spines in developing hippocampal neurons. Irisin treatment increased mitochondrial respiration and mitochondrial membrane potential, but not reactive oxygen species production in an in vitro model of developing hippocampal neurons. Irisin treatment also increased the expression of UCP2, UCP4, and UCP5. Knockdown of UCP2, UCP4, and UCP5 exerted differential effects on basal and irisin-stimulated phenotypes in cultured neurons, while overexpression of UCP2, UCP4, or UCP5 exerted differential effects on basal mitochondrial membrane potential, reactive oxygen species levels, and synaptogenesis. Together, these data suggest a role for irisin in regulating neuronal mitochondrial function through a UCP-dependent mechanism to support synaptogenesis during hippocampal development.