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To sum up, the intricate relationship between autophagy and steroidogenesis within the endocrine system represents a burgeoning field of research with vast clinical implications. Investigating the role of autophagy in human Leydig and GCs, especially in pathological conditions like endometriosis, polycystic ovary syndrome, or testicular disorders, will provide invaluable clinical insights. It is also crucial to understand the underlying molecular mechanisms behind changes in hormone levels seen with exposure to EDCs like bisphenol A. Understanding how EDCs affect hormone production could help us identify ways to protect reproductive health. In addition, delving deeper into the molecular mechanisms underlying the interplay between autophagy and steroidogenesis will be important. The intricate balance between autophagy and steroidogenesis has profound implications for understanding fertility, aging-related endocrine disorders, and potential therapeutic interventions. Furthermore, insights into the regulatory mechanisms of autophagy, such as the involvement of specific genes, signaling pathways, and external factors, provide a comprehensive view of its orchestration within the endocrine system.
AMPK mediates autophagy in Leydig cells (LCs) upon the HsCG challenge. 3-methyladenine and bafilomycin A 1 regulate HsCG-induced autophagy in Leydig cells (LCs). These events led to reduced mRNA methylation levels of N6-methyladenosine (m6A) and enhanced autophagy in LCs. This process increases cholesterol uptake and enhances testosterone synthesis. In vitro investigations have shown that SIRT1 can affect the level of autophagy, cholesterol uptake as well as testosterone release. This process resulted in increased cholesterol intake and enhanced testosterone production.
Additionally, TBC1D20 regulates the formation of acrosomes via facilitating autophagy flux . Concretely, apical ES is localized at the contact surface between the Sertoli cell and the spermatids, and it is tightly connected to the sperm head via the acrosome, being an active participant in spermatozoa head shaping . Thus, energy imbalance, hyperthermia, and hypoxia all induce autophagy during spermatogenesis, while the inhibition of autophagy often relies on chemical inhibitors. Increased scrotal temperature generates testicular heat stress and induces testicular autophagy, later causing spermatogenic arrest . Additionally, amino acid supplementation is an efficient and effective strategy to increase spermatozoa quality, depending on the activation of autophagy .
With the development of LCs from stem LCs to adult LCs, we observed a gradual decrease of m6A levels (Figure 4A). Furthermore, we also recorded upregulated expression of CAMKK2 and downregulated expression of PPM1A in adult LCs in comparison to stem LCs by western blotting and immunofluorescence assays (Figure 3Fand S5). The cell extracts were subjected to western blotting and quantitative analysis. Consistently, we confirmed the increased expression of p-PRKAA2 Thr172 in mouse LCs during development, peaking in adult LCs, by immunofluorescence assay (Figure 3D).
Decreasing levels might be caused by either increased consumption or decreased supply. In autophagy-deficient testes, Filipin signals were notably decreased compared with control groups (Fig. 3, C and D). Because ∼10% of testosterone is synthesized in the adrenal gland and SF1-Cre is also expressed in this gland, we also studied the effect of Atg5 and Atg7 knockout on the adrenal gland. Surprisingly, LDs clearly decreased in autophagy-deficient testes compared with control groups (Fig. 3, A and B), in complete contrast with our working hypothesis and previous results obtained from hepatocytes (Singh et al., 2009). In autophagy-deficient mice, the LH and follicle-stimulating hormone (FSH) concentrations in serum were similar to those in the control groups (Fig. S1, D–G). A decline in testosterone in the serum commonly reflects extrinsic factors, intrinsic factors, or both (Chen et al., 2009; Midzak et al., 2009). Thus, these autophagy-deficient mice might serve as a novel LOH animal model.
While selective autophagy is easier to explain, it refers to the degradation of a specific substrate . With the help of chaperone proteins, selective proteins can be targeted and translocated to the lysosomal lumen, a process known as chaperone-mediated autophagy. Based on all of these observations, C de Duve defined this mode of delivery of cytoplasmic materials to the lysosomes for degradation as "autophagy", which means self-eating in Greek, in 1963 . At present, the involvement of autophagy in testicular function has received a lot of attention, but there are no systematic studies reporting on autophagy in male reproduction. There are data showing that stages VII-VIII of the spermatogenic cycle exhibit high levels of autophagy in SCs for the stress conditions, such as androgen receptor (AR) suppression, lipid accumulation, and mitochondrial damage.
In hCG-treated Leydig cells, NHERF2 clearly colocalized with LC3 as shown by immunofluorescence (Fig. 8 E). Indeed, we found that testosterone synthesis was promoted by hCG treatment (Fig. 8 A). To test this possibility, isolated Leydig cells were directly treated with human chorionic Gn (hCG), the pituitary analogue of LH. (F and G) The accumulation of NHERF2 in autophagy-deficient Leydig cells down-regulated SR-BI as well as SR-BI negatively correlated with NHERF2 in control Leydig cells. Plots show absorption curves of DiI-HDL in autophagy-deficient and control Leydig cells infected by Nherf2 shRNA virus and control virus. (I) NHERF2 is accumulated in autophagy-deficient Leydig cells. (E and G) NHERF2 was stabilized in autophagy-deficient Leydig cells.
Non-specific proteins were blocked, and incubation of the PVDF membranes was carried out overnight with recommended concentrations of primary antibodies at 4 °C. Protein samples were loaded as 20 µg/well to Mini-PROTEAN® TGX™ gels (Bio-Rad), and the transfer of proteins was performed onto the PVDF membrane. Cells were harvested, and protein quantification was performed via a BCA protein assay kit (ThermoFisher). Quantitative real-time expressions of mRNAs of interest were detected and compared by using the Light Cycler 480 SYBR Green I Master (Roche, Germany). Recombinant hormones (hCG, LH and FSH) and pharmacological autophagy inhibitors (chloroquine and vinblastine) were added to the culture media at indicated concentrations. This cell line was a gift from Dr. Ikara Iwase (Nagoya University, Japan).
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