bims-amsmem 2023-04-09 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–04–09
nine papers selected by
Dipsikha Biswas, Københavns Universitet

WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis.
Role of carotenoids in adipose tissue through the AMPK-mediated pathway.
Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
Cyanidin-3-glucoside inhibits ferroptosis in renal tubular cells after ischemia/reperfusion injury via the AMPK pathway.
An update on the molecular mechanism and pharmacological interventions for Ischemia-reperfusion injury by regulating AMPK/mTOR signaling pathway in autophagy.
Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus.
AMPK/mTOR/p70S6K axis prevents apoptosis of Porphyromonas gingivalis-infected gingival epithelial cells via BadSer136 phosphorylation.
Dexmedetomidine Regulates Autophagy via the AMPK/mTOR Pathway to Improve SH-SY5Y-APP Cell Damage Induced by High Glucose.
Translation regulation of specific mRNAs by RPS26 C-terminal RNA-binding tail integrates energy metabolism and AMPK-mTOR signaling.

Commun Biol. 2023 04 03. 6(1): 361

WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis.

Peng Zhang, Hai-Jing Fu, Li-Xia Lv, Chen-Fei Liu, Chang Han, Xiao-Fan Zhao, Jin-Xing Wang.

AMPK plays significant roles in the modulation of metabolic reprogramming and viral infection. However, the detailed mechanism by which AMPK affects viral infection is unclear. The present study aims to determine how AMPK influences white spot syndrome virus (WSSV) infection in shrimp (Marsupenaeus japonicus). Here, we find that AMPK expression and phosphorylation are significantly upregulated in WSSV-infected shrimp. WSSV replication decreases remarkably after knockdown of Ampkα and the shrimp survival rate of AMPK-inhibitor injection shrimp increases significantly, suggesting that AMPK is beneficial for WSSV proliferation. Mechanistically, WSSV infection increases intracellular Ca2+ level, and activates CaMKK, which result in AMPK phosphorylation and partial nuclear translocation. AMPK directly activates mTORC2-AKT signaling pathway to phosphorylate key enzymes of glycolysis in the cytosol and promotes expression of Hif1α to mediate transcription of key glycolytic enzyme genes, both of which lead to increased glycolysis to provide energy for WSSV proliferation. Our findings reveal a novel mechanism by which WSSV exploits the host CaMKK-AMPK-mTORC2 pathway for its proliferation, and suggest that AMPK might be a target for WSSV control in shrimp aquaculture.

DOI: https://doi.org/10.1038/s42003-023-04735-z
Food Funct. 2023 Apr 04.

Role of carotenoids in adipose tissue through the AMPK-mediated pathway.

Yasmin Alaby Martins Ferreira, Giovana Jamar, Débora Estadella, Luciana Pellegrini Pisani.

Diet is a critical factor in controlling adiposity and white adipose tissue (WAT) physiology. A high-fat diet (HFD) alters WAT function and affects AMP-activated protein kinase (AMPK) - a cellular sensor - dysregulating lipolysis and lipid metabolism in adipocytes. Otherwise, AMPK activation may attenuate oxidative stress and inflammation. Interest in natural therapies, such as carotenoid consumption or supplementation, is growing due to their health benefits. Carotenoids are lipophilic pigments present in vegetables and fruits, which cannot be synthesized by the human body. Interventions focused on ameliorating complications induced by a HFD indicate a positive contribution of the carotenoids to the AMPK activation. This review aims to outline the mechanism of carotenoids in the AMPK pathway in adipose tissue and their contribution in regulating adipogenesis. Different carotenoids can act as an agonist of the AMPK signaling pathway, activating upstream kinases, upregulating transcriptional factors, inducing WAT browning, and blocking adipogenesis. In addition, the improvement of some "homeostatic" factors, such as adiponectin, may mediate the AMPK activation induced by carotenoids. With these findings, we encourage clinical trials to confirm the role of carotenoids in the AMPK pathway in a long-term treatment, mainly in obesity cases.

DOI: https://doi.org/10.1039/d2fo03781e
FASEB J. 2023 05;37(5): e22863

Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.

Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Alexander Manta, Ian J Diffey, Vladimir Ljubicic.

  Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor ɣ coactivator-1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.

Keywords:  PGC-1α; autophagy; muscular dystrophy; myogenic regulatory factors; utrophin

DOI:  https://doi.org/10.1096/fj.202201846RR
Mol Med. 2023 Apr 03. 29(1): 42

Cyanidin-3-glucoside inhibits ferroptosis in renal tubular cells after ischemia/reperfusion injury via the AMPK pathway.

Yi-Wei Du, Xiao-Kang Li, Ting-Ting Wang, Lu Zhou, Hui-Rong Li, Lan Feng, Heng Ma, Hong-Bao Liu.

   BACKGROUND: Ferroptosis, which is characterized by lipid peroxidation and iron accumulation, is closely associated with the pathogenesis of acute renal injury (AKI). Cyanidin-3-glucoside (C3G), a typical flavonoid that has anti-inflammatory and antioxidant effects on ischemia‒reperfusion (I/R) injury, can induce AMP-activated protein kinase (AMPK) activation. This study aimed to show that C3G exerts nephroprotective effects against I/R-AKI related ferroptosis by regulating the AMPK pathway.
METHODS: Hypoxia/reoxygenation (H/R)-induced HK-2 cells and I/R-AKI mice were treated with C3G with or without inhibiting AMPK. The level of intracellular free iron, the expression of the ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4), and the levels of the lipid peroxidation markers 4-hydroxynonenal (4-HNE), lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were examined.
RESULTS: We observed the inhibitory effect of C3G on ferroptosis in vitro and in vivo, which was characterized by the reversion of excessive intracellular free iron accumulation, a decrease in 4-HNE, lipid ROS, MDA levels and ACSL4 expression, and an increase in GPX4 expression and glutathione (GSH) levels. Notably, the inhibition of AMPK by CC significantly abrogated the nephroprotective effect of C3G on I/R-AKI models in vivo and in vitro.
CONCLUSION: Our results provide new insight into the nephroprotective effect of C3G on acute I/R-AKI by inhibiting ferroptosis by activating the AMPK pathway.

Keywords:  AMP-activated protein kinase (AMPK); Acute kidney injury (AKI); Cyanidin-3-glucoside (C3G); Ferroptosis; Ischemia; Lipid peroxidation

DOI:  https://doi.org/10.1186/s10020-023-00642-5
Cell Signal. 2023 Mar 31. pii: S0898-6568(23)00079-7. [Epub ahead of print] 110665

An update on the molecular mechanism and pharmacological interventions for Ischemia-reperfusion injury by regulating AMPK/mTOR signaling pathway in autophagy.

Bin Tang, Zhijian Luo, Rong Zhang, Dongmei Zhang, Guojun Nie, Mingxing Li, Yan Dai.

  AMP-activated protein kinase (5'-adenosine monophosphate-activated protein kinase, AMPK)/mammalian target of rapamycin (mTOR) is an important signaling pathway maintaining normal cell function and homeostasis in vivo. The AMPK/mTOR pathway regulates cellular proliferation, autophagy, and apoptosis. Ischemia-reperfusion injury (IRI) is secondary damage that frequently occurs clinically in various disease processes and treatments, and the exacerbated injury during tissue reperfusion increases disease-associated morbidity and mortality. IRI arises from multiple complex pathological mechanisms, among which cell autophagy is a focus of recent research and a new therapeutic target. The activation of AMPK/mTOR signaling in IRI can modulate cellular metabolism and regulate cell proliferation and immune cell differentiation by adjusting gene transcription and protein synthesis. Thus, the AMPK/mTOR signaling pathway has been intensively investigated in studies focused on IRI prevention and treatment. In recent years, AMPK/mTOR pathway-mediated autophagy has been found to play a crucial role in IRI treatment. This article aims to elaborate the action mechanisms of AMPK/mTOR signaling pathway activation in IRI and summarize the progress of AMPK/mTOR-mediated autophagy research in the field of IRI therapy.

Keywords:  AMPK/mTOR autophagy IRI research progress

DOI:  https://doi.org/10.1016/j.cellsig.2023.110665
Signal Transduct Target Ther. 2023 Apr 05. 8(1): 143

Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus.

Junjie Wang, Ziping Qi, Yun Wu, Aoli Wang, Qingwang Liu, Fengming Zou, Beilei Wang, Shuang Qi, Jiangyan Cao, Chen Hu, Chenliang Shi, Qianmao Liang, Li Wang, Jing Liu, Wenchao Wang, Qingsong Liu.

Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

DOI: https://doi.org/10.1038/s41392-023-01352-4
Apoptosis. 2023 Apr 04.

AMPK/mTOR/p70S6K axis prevents apoptosis of Porphyromonas gingivalis-infected gingival epithelial cells via BadSer136 phosphorylation.

Yanchun Wang, Yilong Dong, Wenbo Zhang, Yanmei Wang, Yang Jao, Jianjun Liu, Mingzhu Zhang, Hongbing He.

  Epithelial disruption is the initiation of most infectious disease. Regulation of epithelium apoptosis may play a key role in balance the survival competition between resident bacteria and host cells. The role of the mTOR/p70S6K pathway in preventing apoptosis of human gingival epithelial cells (hGECs) infected with Porphyromonas gingivalis (Pg) was investigated in order to further understand the survival strategy of the epithelial cells in during Pg infecting. hGECs was challenged with Pg for 4, 12, and 24 h. Additionally, hGECs was pretreated with LY294002 (PI3K signaling inhibitor) or Compound C (AMPK inhibitor) for 12 h and exposed them to Pg for 24 h. Subsequently, apoptosis was detected using flow cytometry, and expression and activity of Bcl-2, Bad, Bax, PI3K, AKT, AMPK, mTOR, and p70S6K proteins were analyzed using western blotting. Pg-infecting did not increase apoptosis of hGECs; but the expression ratio of Bad to Bcl-2 was increased after infecting. In contrast, BadSer136 phosphorylation was promoted, accompanied by a significant reduction of mTOR/p70S6K and PI3K/AKT signaling, along with the upregulation of AMPKThr172 signaling. Morrover, the PI3K inhibitor LY294002 promoted Pg-mediated reduction of mTOR/p70S6K expression, and the increase of AMPK signaling and BadSer136 phosphorylation rate, eventually decreasing apoptosis. While Compound C inhibited Pg-mediated activation of AMPK and downregulation of mTOR/p70S6K signaling, significantly reduced the BadSer136 phosphorylation rate, thereby increasing apoptosis. Thus, hGECs prevent apoptosis via an inherent cellular-homeostasis, pro-survival mechanism during Pg infection, the AMPK/mTOR/p70S6K pathway helps prevent apoptosis in hGECs infected with Pg by regulating BadSer136 phosphorylation.

Keywords:  AMPK; BadSer136 phosphorylation; Porphyromonas gingivalis; mTOR; p70S6K pathway

DOI:  https://doi.org/10.1007/s10495-023-01839-z
Neuromolecular Med. 2023 Apr 05.

Dexmedetomidine Regulates Autophagy via the AMPK/mTOR Pathway to Improve SH-SY5Y-APP Cell Damage Induced by High Glucose.

Pinzhong Chen, Xiaohui Chen, Honghong Zhang, Jianghu Chen, Mingxue Lin, Haitao Qian, Fei Gao, Yisheng Chen, Cansheng Gong, Xiaochun Zheng, Ting Zheng.

  Neurodegenerative diseases and postoperative cognitive dysfunction involve the accumulation of β-amyloid peptide (Aβ). High glucose can inhibit autophagy, which facilitates intracellular Aβ clearance. The α2-adrenoreceptor agonist dexmedetomidine (DEX) can provide neuroprotection against several neurological diseases; however, the mechanism remains unclear. This study investigated whether DEX regulated autophagy via the AMPK/mTOR pathway to improve high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells. SH-SY5Y/APP695 cells were cultured with high glucose with/without DEX. To examine the role of autophagy, the autophagy activator rapamycin (RAPA) and autophagy inhibitor 3-methyladenine (3-MA) were used. The selective AMPK inhibitor compound C was used to investigate the involvement of the AMPK pathway. Cell viability and apoptosis were examined by CCK-8 and annexin V-FITC/PI flow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine staining of autophagic vacuoles. Autophagy- and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quantified by western blotting. DEX pretreatment significantly suppressed high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells, as evidenced by the enhanced viability, restoration of cellular morphology, and reduction in apoptotic cells. Furthermore, RAPA had a protective effect similar to that of DEX, but 3-MA eliminated the protective effect of DEX by promoting mTOR activation. Moreover, the AMPK/mTOR pathway was involved in DEX-mediated autophagy. Compound C significantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our findings demonstrated that DEX protected SH-SY5Y/APP695 cells against high glucose-induced neurotoxicity by upregulating autophagy through the AMPK/mTOR pathway, suggesting a role of DEX in treating POCD in diabetic patients.

Keywords:  AMPK; Apoptosis; Autophagy; Dexmedetomidine; High glucose

DOI:  https://doi.org/10.1007/s12017-023-08745-2
Nucleic Acids Res. 2023 Apr 04. pii: gkad238. [Epub ahead of print]

Translation regulation of specific mRNAs by RPS26 C-terminal RNA-binding tail integrates energy metabolism and AMPK-mTOR signaling.

Tal Havkin-Solomon, Davide Fraticelli, Anat Bahat, Daniel Hayat, Nina Reuven, Yosef Shaul, Rivka Dikstein.

Increasing evidence suggests that ribosome composition and modifications contribute to translation control. Whether direct mRNA binding by ribosomal proteins regulates the translation of specific mRNA and contributes to ribosome specialization has been poorly investigated. Here, we used CRISPR-Cas9 to mutate the RPS26 C-terminus (RPS26dC) predicted to bind AUG upstream nucleotides at the exit channel. RPS26 binding to positions -10 to -16 of short 5' untranslated region (5'UTR) mRNAs exerts positive and negative effects on translation directed by Kozak and Translation Initiator of Short 5'UTR (TISU), respectively. Consistent with that, shortening the 5'UTR from 16 to 10 nt diminished Kozak and enhanced TISU-driven translation. As TISU is resistant and Kozak is sensitive to energy stress, we examined stress responses and found that the RPS26dC mutation confers resistance to glucose starvation and mTOR inhibition. Furthermore, the basal mTOR activity is reduced while AMP-activated protein kinase is activated in RPS26dC cells, mirroring energy-deprived wild-type (WT) cells. Likewise, the translatome of RPS26dC cells is correlated to glucose-starved WT cells. Our findings uncover the central roles of RPS26 C-terminal RNA binding in energy metabolism, in the translation of mRNAs bearing specific features and in the translation tolerance of TISU genes to energy stress.

DOI: https://doi.org/10.1093/nar/gkad238