SIRT3 deficiency is resistant to autophagy‐dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels

Abstract

Ferroptosis, an autophagy‐dependent cell death, is characterized by lipid peroxidation and iron accumulation, closely associated with pathogenesis of gestational diabetes mellitus (GDM). Sirtuin 3 (SIRT3) has positive regulation on phosphorylation of activated protein kinase (AMPK), related to maintenance of cellular redox homeostasis. However, whether SIRT3 can confer autophagy by activating the AMPK‐mTOR pathway and consequently promote induction of ferroptosis is unknown. We used human trophoblastic cell line HTR8/SVneo and porcine trophoblastic cell line pTr2 to deterimine the mechanism of SIRT3 on autophagy and ferroptosis. The expression of SIRT3 protein was significantly elevated in trophoblastic cells exposed to high concentrations of glucose and ferroptosis‐inducing compounds. Increased SIRT3 expression contributed to classical ferroptotic events and autophagy activation, whereas SIRT3 silencing led to resistance against both ferroptosis and autophagy. In addition, autophagy inhibition impaired SIRT3‐enhanced ferroptosis. On the contrary, autophagy induction had a synergistic effect with SIRT3. Based on mechanistic investigations, SIRT3 depletion inhibited activation of the AMPK‐mTOR pathway and enhanced glutathione peroxidase 4 (GPX4) level, thereby suppressing autophagy and ferroptosis. Furthermore, depletion of AMPK blocked induction of ferroptosis in trophoblasts. We concluded that upregulated SIRT3‐enhanced autophagy activation by promoting AMPK‐mTOR pathway and decreasing GPX4 level to induce ferroptosis in trophoblastic cells. SIRT3 deficiency was resistant to high glucose‐ and erastin‐induced autophagy‐dependent ferroptosis and is, therefore, a potential therapeutic approach for treating GDM.

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

“…A recent study showed that glucose depletion prevents ferroptosis caused by erastin and RSL3 in immortalized mouse embryonic fibroblasts (MEFs) by activating AMP-activated protein kinase (AMPK)-mediated phosphorylation of acetyl-CoA carboxylase (Lee et al, 2020). In contrast, AMPK-mediated phosphorylation of Beclin 1 promotes ferroptotic cell death in colon cancer cells (e.g., PANC1; Song et al, 2018a) and noncancer cells (e.g., HTR8/Svneo; Han et al, 2020)). Moreover, AMPK-mediated stearoyl-CoA desaturase (SCD/SCD1) downregulation promotes ferroptosis in hepatocellular carcinoma cells by inhibiting production of monounsaturated fatty acids (MUFAs) (Zhao et al, 2020).…”

High glucose suppresses autophagy through the AMPK pathway while it induces autophagy via oxidative stress in chondrocytes

“…By contrast, Zhao et al established that excessive autophagy in H9c2 cells was induced in a HG medium 26 . Furthermore, two studies reported that high concentrations of glucose facilitated autophagy activation in trophoblast cell lines and the cardiomyocyte cell lines 27 , 28 . To the best of our knowledge, the effects of HG on autophagy in chondrocytes remain indeterminate.…”

Ammonium Ferric Citrate induced Ferroptosis in Non-Small-Cell Lung Carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity

“…Autophagy is abnormally high in tumour cells, which is assumed to be closely related to the abnormally active cell division and metabolism [28][29][30][31]. However, many recent studies have demonstrated that autophagy and ferroptosis are not two independent events but are inextricably linked [31][32][33][34][35]. Autophagy and ferroptosis are mutually reinforcing and interdependent, and they exhibit different interrelationships in different individuals, cells, and disease processes [33,34].…”