Fig. 7: The administration of MitoQ prenatally rescues defective social recognition of GPR50-deficient mice.

A Schematic description of experimental procedures. Gpr50^−/y mice were administrated with MitoQ (5 mg/kg/day) starting from E14. MitoQ treatment continued after the pubs were weaned until behavioral tests. The control mice were fed a standard diet. B–E Three chamber tests in Gpr50^+/y and Gpr50^−/y mice. Gpr50^−/y mice were treated with MitoQ as a rescue group. Time the mice spent in chambers containing either Object (Ob in B) or Familiar mice (F in D) versus Stranger (S in B, D) mice. Time the mice spent interacting with either Object (Ob in C) or Familiar mice (F in E) versus Stranger (S in C, E) mice. One-way ANOVA (F_{8, 117} = 68.037, p = 0.000) followed by LSD post hoc tests for Gpr50^+/y Object versus Gpr50^+/y Stranger (p = 0.001), Gpr50^−/y Object versus Gpr50^−/y Stranger (p = 0.000), Gpr50^−/y +MitoQ Object versus Gpr50^−/y +MitoQ Stranger (p = 0.000) (B). One-way ANOVA (F_{8, 123} = 70.486, p = 0.000) followed by LSD post hoc tests for Gpr50^+/y Familiar versus Gpr50^+/y Stranger (p = 0.001), Gpr50^−/y Familiar versus Gpr50^−/y Stranger (p = 0.226), Gpr50^−/y +MitoQ Familiar versus Gpr50^−/y+MitoQ Stranger (p = 0.000) (D). One-way ANOVA (F_{5, 78} = 32.580, p = 0.000) followed by LSD post hoc tests for Gpr50^−/y Object versus Gpr50^−/y Stranger (p = 0.000), Gpr50^−/y Object versus Gpr50^−/y Stranger (p = 0.000), Gpr50^−/y+MitoQ Object versus Gpr50^−/y+MitoQ Stranger (p = 0.000) (C). One-way ANOVA (F_{5, 78} = 5.273, p = 0.000) followed by LSD post hoc tests for Gpr50^+/y Familiar versus Gpr50^+/y Stranger (p = 0.014), Gpr50^−/y Familiar versus Gpr50^−/y Stranger (p = 0.610), Gpr50^−/y+MitoQ Familiar versus Gpr50^−/y+MitoQ Stranger (p = 0.000) (E). n = 14–15 mice per genotype (B–E). F Schematic summary of the role of GPR50-mediated mitophagy in neuronal development. GPR50 is a novel mitophagy receptor. Upon mitophagy stress, such as the depolarization of mitochondrial membrane induced by either CCCP or high OXPHOS, GPR50 is recruited to the damaged mitochondria, where it interacts with other mitophagy regulators and facilitates the recruitment of the assembling autophagosomes, promoting mitophagy. In this way, GPR50 maintains mitochondrial metabolism in the developing neurons. Mutations at either Δ502-505 or T532A, disrupts the binding capability of GPR50 to LC3 and the recruitment of GPR50 to the damaged mitochondria, thus attenuating GPR50-mediated mitophagy, resulting in insufficient ATP production and overproduction of ROS, leading to defective social recognition behaviors of the mouse. The administration of mitoQ prenatally rescues the defective social recognition behaviors of GPR50-deficient mice. Data are presented as mean ± SEM.*p < 0.05; **p < 0.01; ***p < 0.001. n.s, non-significance.