GPR50 is an orphan G protein-coupled receptor located on chromosome X that functions in neuronal development and mitochondrial homeostasis. As a mitophagy receptor, GPR50 harbors an LC3-interacting region and is recruited to depolarized mitochondrial membranes during stress, facilitating selective autophagy of damaged mitochondria to maintain oxidative phosphorylation during neuronal development 1. GPR50 deficiency causes mitochondrial accumulation and impaired ATP production, leading to excessive reactive oxygen species generation and compromised neuronal development 1. Additionally, GPR50 restrains neurite outgrowth and cell migration by activating the G12/13 protein-RhoA signaling pathway 2, functioning independently of the Nogo-A pathway 2. In response to neurotrophic signals, GPR50 induction via ERK-dependent signaling promotes PACAP-induced neuritogenesis 3, occurring in a RapGEF2-dependent manner 3. GPR50 expression occurs in hypothalamic neurons, tanycytes, and median eminence tissue 4, suggesting roles in hypothalamic-pituitary axis regulation. GPR50 genetic variants associate with altered lipid metabolism, including elevated triglyceride and reduced HDL-cholesterol levels 5, and are implicated as risk factors for neuropsychiatric disorders 2.