bims-amsmem 2023-07-23 papers

Issue of 2023–07–23
five papers selected by
Dipsikha Biswas, Københavns Universitet

Cell Res. 2023 Jul 17.

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.

Yuan-Li Ai, Wei-Jia Wang, Fan-Jian Liu, Wei Fang, Hang-Zi Chen, Liu-Zheng Wu, Xuehui Hong, Yuekun Zhu, Ci-Xiong Zhang, Long-Yu Liu, Wen-Bin Hong, Bo Zhou, Qi-Tao Chen, Qiao Wu.

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

DOI: https://doi.org/10.1038/s41422-023-00848-6

Biomed Pharmacother. 2023 Jul 18. pii: S0753-3322(23)00949-6. [Epub ahead of print]165 115158

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice.

Suchada Kaewin, Wanangkan Poolsri, Gül Gizem Korkut, Jaakko Patrakka, Thitinan Aiebchun, Thanyada Rungrotmongkol, Titiwat Sungkaworn, I Butu Sukanadi, Warinthorn Chavasiri, Chatchai Muanprasat.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase β (CaMKKβ) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

Keywords: AMPK activator; Albuminuria; Chalcone derivatives; Diabetic nephropathy; db/db mice

DOI: https://doi.org/10.1016/j.biopha.2023.115158

NPJ Syst Biol Appl. 2023 07 17. 9(1): 34

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling.

A Leung, P Rangamani.

Neuronal energy consumption is vital for information processing and memory formation in synapses. The brain consists of just 2% of the human body's mass, but consumes almost 20% of the body's energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of synaptic transmission. Here, we develop a computational model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that frequencies of glutamate stimulus over 10 Hz perturb AMPK and mTOR oscillations at higher magnitudes by up to 36% and change the area under curve (AUC) by 5%. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning, and synaptic plasticity.

DOI: https://doi.org/10.1038/s41540-023-00295-4

Biochim Biophys Acta Mol Cell Res. 2023 Jul 16. pii: S0167-4889(23)00109-X. [Epub ahead of print]1870(7): 119537

Therapeutic strategies targeting AMPK-dependent autophagy in cancer cells.

Wenbin Yuan, Wanyi Fang, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Declan William Ali, Marek Michalak, Xing-Zhen Chen, Cefan Zhou, Jingfeng Tang.

Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.

Keywords: AMPK; Autophagy; Cancer therapy; Metabolism; Tumor

DOI: https://doi.org/10.1016/j.bbamcr.2023.119537

BMC Endocr Disord. 2023 Jul 17. 23(1): 152

Effects of UBE3A on the insulin resistance in polycystic ovary syndrome through the ubiquitination of AMPK.

Ning Ma, Jing Zhou, Zhi Zhou, Bangbei Wan, Weiying Lu.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive hormonal abnormality and a metabolic disorder, which is frequently associated with insulin resistance (IR). We aim to investigate the potential therapeutic effects of Ubiquitin-protein ligase E3A (UBE3A) on IR in the PCOS rats via Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation.
METHODS: The PCOS and IR rats model was established by dehydroepiandrosterone (DHEA) and high fat diet (HFD) treatment, and the fat rate, glucose tolerance and insulin tolerance were measured. The IR rats numbers were calculated. Besides, the mRNA levels of glucose transporter 4 (GLUT4) and UBE3A were detected by RT-qPCR. Furthermore, the relationship between was demonstrated by co-IP assay. The phosphorylation and ubiquitination of AMPK were analyzed by western blot.
RESULTS: UBE3A was up-regulated in the PCOS rats. UBE3A knockdown significantly decreased the fat rate, glucose tolerance and insulin tolerance in the PCOS and IR rats. Additionally, the GLUT4 levels were significantly increased in PCOS + IR rats. Besides, after UBE3A knockdown, the IR rats were decreased, the p-IRS1 and p-AKT levels were significantly up-regulated. Furthermore, UBE3A knockdown enhanced phosphorylation of AMPK through decreasing the ubiquitination of AMPK. AMPK knockdown reversed the role of UBE3A knockdown in the PCOS + IR rats.
CONCLUSIONS: UBE3A knockdown inhibited the IR in PCOS rats through targeting AMPK. Our study indicated that UBE3A might become a potential biological target for the clinical treatment of PCOS.

Keywords: Denosine 5‘-monophosphate (AMP)-activated protein kinase; Insulin resistance; Polycystic ovary syndrome; Ubiquitin-protein ligase E3A

DOI: https://doi.org/10.1186/s12902-023-01400-8