Mitochondrial dysfunction can lead to oxidative stress that inhibits the Bcl-2-related signaling pathway, resulting in decreased CREB transcriptional activity and downregulation of BDNF expression, which in turn reduces the activity of the PI3K/Akt and extracellular regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathways, thereby weakening cellular antioxidant stress and energy metabolism [11], affecting neural plasticity and mediating the onset of depression [87]. This evidence concerns the gene CREB1 and major depressive disorder.