The Expression of the Low-Density Lipoprotein Receptor Modulates the Effects of Hypogonadism on Mitochondrial Activity in Different Brain Domains

Abstract

Background: Testosterone deficiency (TD), brain mitochondrial uncoupling protein 2 (UCP2), and the low-density lipoprotein receptor (LDLR) are independently linked to the triggering of several behavioral disorders. Here, we investigated how TD impacts mitochondrial activity and apoptosis in different brain domains in the presence and absence of LDLR. Materials and Methods: Sham-operated or surgically castrated C57BL/6 or LDLR-deficient (Ldlr−/−) mice were fed a western-type diet for 12 weeks. Then, mitochondrial UCP2 and cytochrome c (Cytc) relative protein levels were measured as markers of uncoupling and oxidative phosphorylation, respectively, in tissue specimens from different brain domains. The ratio of the relative cytoplasmic Cytc levels over the relative mitochondrial Cytc levels (CM ratio) was used as a biochemical marker of Cytc-dependent apoptosis. Results: In cerebral hemispheres and the cerebellum area of both C57BL/6 and Ldlr−/− mice, castration resulted in increased UCP2, suggesting protection from hypogonadism-induced oxidative stress. In the broader midbrain, castration reduced UCP2 expression in C57BL/6 mice but not in Ldlr−/− mice, suggesting that LDLR deficiency protects from oxidative stress in this region. CM ratio was ≤1 after castration in these three brain domains, suggesting increased protection from Cytc-dependent apoptosis. In diencephalon, castration had no effect on UCP2 and CM ratio in C57BL/6 mice but led to increased UCP2 expression and increased CM ratio in Ldlr−/− mice, suggesting an increase in apoptosis in the diencephalon of castrated Ldlr−/− mice. Conclusions: TD in Ldlr−/− mice fed a western-type diet is associated with protection from oxidative stress but could contribute to the emergence of behavioral or systemic impairments linked to apoptosis in the diencephalon.