Inactivation of glycogen synthase kinase-3α is required for mitochondria-mediated apoptotic germ cell phagocytosis in Sertoli cells

Abstract

The rapid and efficient clearance of apoptotic germ cells (GCs) by Sertoli cells (SCs) is important for spermatogenesis. High mitochondrial activity in phagocytes is critical for continued clearance of apoptotic cells. However, the underlying molecular mechanism is poorly understood. Glycogen synthase kinase-3α (GSK3α) is a protein kinase that participates in the regulation of mitochondrial activity. Immunohistochemistry evidenced the predominant presence of the Ser21 phosphorylation GSK3α (inactivation) signal in SCs. Heat shock-induced apoptosis of GCs and dephosphorylation of GSK3α in SCs is a perfect model to investigate the role of GSK3α in phagocytic action. The number of apoptotic GCs was significantly lower in GSK3α inhibitor pre-treated mice with HS compared to normal control. In vitro phagocytosis assays shown that the phagocytic activity in GSK3α activated SCs was downregulated, while GSK3α inhibitor supplementation restored this process. Moreover, GSK3α activation participates in the alteration of the mitochondrial ultrastructure and activity. In particular, GSK3α activation inhibits mitochondrial fission via phosphorylation of dynamin related protein 1 at Ser637. Changes of mitochondrial activity resulted in the accumulation of lipid droplets and the alteration of metabolism pattern in SCs. In summary, our results demonstrate that inactivation of GSK3α is required for mitochondria-mediated apoptotic GCs phagocytosis in SCs.

Dysfunction in Sertoli cells participates in glucocorticoid‐induced impairment of spermatogenesis

“…We and others have reported that the mitochondrial membrane potential is a key determinant of apoptotic cell clearance in Sertoli cells (Park et al, 2011; Gong et al, 2018). In the present study, corticosterone resulted in decreased mitochondrial membrane potential in Sertoli cells.…”

Melatonin modulates Nrf2 activity to protect porcine pre‐pubertal Sertoli cells from the abnormal H2O2 generation and reductive stress effects of cadmium

“…Apparently, this efflux mechanism maintains the intracellular levels of this species relatively stable, even if increased (Figure 1D), during the response to Cd toxicity. These findings highlight the phagocyte-like properties of these cells upon stimulation of stress pathways by the exposure to either xenobiotics and oxidative stress, 27,[46][47][48] as well as to physiological stimuli, such as during ectoplasmic specialization to support all phases of germ cell development and maturity. 49,50 MLT co-treatment significantly prevented the effects of Cd on cell viability and abnormal ROS production (Figure 1C,D), confirming the cytoprotective function and antioxidant properties of this hormonal substance 20 and its relevance in preventing Cd toxicity.…”

Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice

“…Previous studies revealed that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway enhances the mitochondrial membrane potential and inhibits the production of reactive oxygen species, leading to regulate cellular processes and memory deficits [27, 28]. PI3K can activate downstream kinase Akt through phosphorylation at the ser473 residue and subsequently leading to phosphorylation of its downstream substrate GSK3β at ser9 residue, thus inhibits the activity of GSK3β [29]. In addition, Bcl-2, and cleaved-caspase-3 are important mediators of AD that are relevant to the regulation of mitochondrial apoptosis as the downstream targets of Akt [30, 31].…”