bims-amsmem 2023-01-29 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–01–29
ten papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK phosphorylates ZDHHC13 to increase MC1R activity and suppress melanomagenesis.
Ribavirin extends the lifespan of Caenorhabditis elegans through AMPK-TOR Signaling.
Kirenol inhibits inflammation challenged by lipopolysaccharide through the AMPK-mTOR-ULK1 autophagy pathway.
AMPK is required for recovery from metabolic stress induced by ultrasound microbubble treatment.
Hesperidin enhances intestinal barrier function in Caco-2 cell monolayers via AMPK-mediated tight junction-related proteins.
Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.
Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice.
AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation.
Ellagic acid induces apoptosis and autophagy in colon cancer through the AMPK/mTOR pathway.
Resveratrol protects osteocytes against oxidative stress in ovariectomized rats through AMPK/JNK1-dependent pathway leading to promotion of autophagy and inhibition of apoptosis.

Cancer Res. 2023 Jan 26. pii: CAN-22-2595. [Epub ahead of print]

AMPK phosphorylates ZDHHC13 to increase MC1R activity and suppress melanomagenesis.

Yu Sun, Xin Li, Chengqian Yin, Judy Zhang, Ershang Liang, Xianfang Wu, Ying Ni, Joshua Arbesman, Colin R Goding, Shuyang Chen.

Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC-variants) are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase ZDHHC13. A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in red-heads. Here we report that AMPK phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in red-heads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2595
Eur J Pharmacol. 2023 Jan 24. pii: S0014-2999(23)00059-6. [Epub ahead of print] 175548

Ribavirin extends the lifespan of Caenorhabditis elegans through AMPK-TOR Signaling.

Ganlan Zhang, Hui Liu, Ting Xue, Xiangming Kong, Dongmei Tian, Libo Luo, Yanhua Yang, Keqing Xu, Youheng Wei, Ziheng Zhuang.

  Aging is a process accompanied by widespread degenerative changes which are a major cause of human disease and disability. One goal of aging research is to develop interventions or drugs that can extend organism lifespan and treat age-related diseases. Here, we report the identification of a broad spectrum anti-viral agent, ribavirin, as a potential pharmacological aging intervention. Ribavirin extended the lifespan and healthspan of Caenorhabditis elegans by inhibiting Target of Rapamycin (TOR) signaling and activating AMP-activated protein kinase (AMPK). Moreover, our data indicate that ribavirin activated AMPK by reducing the levels of adenosine triphosphate (ATP) and lysosomal v-ATPase-Ragulator-AXIN Complex. Thus, our studies successfully identify ribavirin as a potential anti-aging drug, and indicate that its anti-aging effect is mediated via AMPK-TOR signaling.

Keywords:  AMPK; Aging; Caenorhabditis elegans; Lifespan; Ribavirin; TOR

DOI:  https://doi.org/10.1016/j.ejphar.2023.175548
Int Immunopharmacol. 2023 Jan 25. pii: S1567-5769(23)00057-7. [Epub ahead of print]116 109734

Kirenol inhibits inflammation challenged by lipopolysaccharide through the AMPK-mTOR-ULK1 autophagy pathway.

Juan Xiao, Xiaofang Shen, Ruiming Kou, Ke Wang, Lihong Zhai, Lu Ding, Huabo Chen, Chun Mao.

  Kirenol is a bioactive substance isolated from Herba Siegesbeckiae. Although the anti-inflammatory activity of kirenol has been well documented, its role in autophagy remains unknown. The present study aimed to investigate the protective role of kirenol on inflammation challenged by lipopolysaccharide (LPS) in acute lung injury (ALI) cell and mouse models and unravel the underlying mechanisms, with a particular focus on autophagy. For this purpose, an ALI cell and mouse models were established, and the effects of kirenol on the expression of molecules related to inflammation and autophagy were examined. The present results revealed that kirenol could significantly inhibit inflammatory cytokines secretion in cells and in the mice injured by LPS; this effect may be attributed to enhanced autophagy as evidenced by the up-regulation of LC3-II and the down-regulation of p62 both in vitro and in vivo. Phosphorylated AMPK and ULK1 increased, while phosphorylated mTOR decreased in the kirenol-treated ALI cell model. Moreover, inhibition of autophagy using AMPK inhibitor or 3-MA or chloroquine (CQ) reversed the anti-inflammatory and autophagy-enhancement effects of kirenol exposure in vitro, indicating that kirenol could enhance autophagy by activating the AMPK-mTOR-ULK1 pathway. The results of RNA sequencing suggested that kirenol was strongly related to the biological functions of acute inflammatory response and the AMPK signaling pathway. Further in vivo ALI mouse model studies demonstrated the protective role of kirenol against lung inflammation, such as improved histopathology, decreased lung edema, and leukocyte infiltration were abolished by 3-MA. These findings implicate that kirenol can inhibit LPS-induced inflammation via the AMPK-mTOR-ULK1 autophagy pathway.

Keywords:  AMPK-mTOR-ULK1; Acute lung injury; Autophagy; Kirenol

DOI:  https://doi.org/10.1016/j.intimp.2023.109734
iScience. 2023 Feb 17. 26(2): 105883

AMPK is required for recovery from metabolic stress induced by ultrasound microbubble treatment.

Louis Lo, Oro Uchenunu, Roberto J Botelho, Costin N Antonescu, Raffi Karshafian.

  Ultrasound-stimulated microbubble (USMB) treatment is a promising strategy for cancer therapy. USMB promotes drug delivery by sonoporation and enhanced endocytosis, and also impairs cell viability. However, USMB elicits heterogeneous effects on cell viability, with apparently minimal effects on a subset of cells. This suggests that mechanisms of adaptation following USMB allow some cells to survive and/or proliferate. Herein, we used several triple negative breast cancer cells to identify the molecular mechanisms of adaptation to USMB-induced stress. We found that USMB alters steady-state levels of amino acids, glycolytic intermediates, and citric acid cycle intermediates, suggesting that USMB imposes metabolic stress on cells. USMB treatment acutely reduces ATP levels and stimulates the phosphorylation and activation of AMP-activated protein kinase (AMPK). AMPK is required to restore ATP levels and support cell proliferation post-USMB treatment. These results suggest that AMPK and metabolic perturbations are likely determinants of the antineoplastic efficacy of USMB treatment.

Keywords:  Biological sciences; Biotechnology; Cell; Cellular physiology

DOI:  https://doi.org/10.1016/j.isci.2022.105883
FEBS Open Bio. 2023 Jan 26.

Hesperidin enhances intestinal barrier function in Caco-2 cell monolayers via AMPK-mediated tight junction-related proteins.

Ha-Young Park, Jin-Hee Yu.

  The intestinal epithelium is a single cell layer on the mucosal surface that absorbs food-derived nutrients and functions as a barrier that protects mucosal integrity. Hesperidin (hesperetin-7-rhamnoglucoside) is a flavanone glycoside comprised of the flavanone hesperetin and the disaccharide rutinose, which has various physiological benefits, including antioxidative, anti-inflammatory, and anti-allergic effects. Here, we used human intestinal Caco-2 cell monolayers to examine the effect of hesperidin on intestinal barrier function. Hesperidin-treated Caco-2 cell monolayers displayed enhanced intestinal barrier integrity, as indicated by an increase in transepithelial electrical resistance (TEER) and a decreased apparent permeability (Papp ) for fluorescein. Hesperidin elevated the mRNA and protein levels of occludin, MarvelD3, JAM-1, claudin-1, and claudin-4, which are encoded by tight junction (TJ)-related genes. Moreover, hesperidin significantly increased the phosphorylation of AMP-activated protein kinase (AMPK), indicating improved intestinal barrier function. Thus, our results suggest that hesperidin enhances intestinal barrier function by increasing the expression of TJ-related occludin, MarvelD3, JAM-1, and claudin-1 via AMPK activation in human intestinal Caco-2 cells.

Keywords:  AMP-activated protein kinase; Caco-2 cells; Hesperidin; Paracellular transport; Tight junction

DOI:  https://doi.org/10.1002/2211-5463.13564
Nat Commun. 2023 Jan 26. 14(1): 422

Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.

Yaqiong Li, Zhipeng Niu, Jichao Yang, Xuke Yang, Yukun Chen, Yingying Li, Xiaohan Liang, Jingwen Zhang, Fuqiang Fan, Ping Wu, Chao Peng, Bang Shen.

The ubiquitous pathogen Toxoplasma gondii has a complex lifestyle with different metabolic activities at different stages that are intimately linked to the parasitic environments. Here we identified the eukaryotic regulator of cellular homeostasis AMP-activated protein kinase (AMPK) in Toxoplasma and discovered its role in metabolic programming during parasite's lytic cycle. The catalytic subunit AMPKα is quickly phosphorylated after the release of intracellular parasites to extracellular environments, driving energy-producing catabolism to power parasite motility and invasion into host cells. Once inside host cells, AMPKα phosphorylation is reduced to basal level to promote a balance between energy production and biomass synthesis, allowing robust parasite replication. AMPKγ depletion abolishes AMPKα phosphorylation and suppresses parasite growth, which can be partially rescued by overexpressing wildtype AMPKα but not the phosphorylation mutants. Thus, through the cyclic reprogramming by AMPK, the parasites' metabolic needs at each stage are satisfied and the lytic cycle progresses robustly.

DOI: https://doi.org/10.1038/s41467-023-36084-0
Front Pharmacol. 2022 ;13 1038802

Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice.

Panpan Zhao, Xiaomin Li, Qiankun Yang, Yingzhi Lu, Guanglu Wang, Haitao Yang, Jingquan Dong, Honggang Zhang.

  This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate the underlying mechanism. SAE mice models were developed and treated with malvidin for subsequently protective effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100β and NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity with elevated tight junction proteins, and decreased evans blue leakage, and finally protect SAE mice from brain injury. Mechanistically, malvidin prevented cerebrum from mitochondrial dysfunction with enhanced JC-1 aggregates and ATP levels, and ROS accumulation with decreased lipid peroxidation and increased antioxidant enzymes. UCP2 protein levels were found to be decreased after LPS stimulation in the cerebrum and BV-2 cells, and malvidin recovered its levels in a ROS dependent manner. In vivo inhibition of UCP2 with genipin or in vitro interference with siRNA UCP2 both disrupted the mitochondrial membrane potential, decreased ATP levels and intensified DCF signals, being a key target for malvidin. Moreover, dorsomorphin block assays verified that malvidin upregulated UCP2 expression through phosphorylating AMPK in SAE models. Also, malvidin alleviated SAE progression through inhibition of ROS-dependent NLRP3 inflammasome activation mediated serum pro-inflammatory cytokines secretion and mitochondrial pathway mediated apoptosis with weakened apoptosis body formation and tunel positive signals, and decreased Bax, cytochrome C, caspase-3 and increased Bcl-2 protein levels. Overall, this study illustrated that malvidin targeted AMPK-α/UCP2 axis to restore LPS-induced mitochondrial dysfunction and alleviate ROS accumulation, which further inhibits NLRP3 inflammasome activation and mitochondrial apoptosis in a ROS dependent way, and ultimately protected SAE mice, providing a reference for the targeted development of SAE prophylactic approach.

Keywords:  AMPK-α; ROS; UCP2; malvidin; mitochondrial dysfunction; sepsis-associated encephalopathy

DOI:  https://doi.org/10.3389/fphar.2022.1038802
Cell Biosci. 2023 Jan 22. 13(1): 15

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-κB activation.

Jing Cai, Yue Wang, Xinfa Wang, Zihe Ai, Tianyuan Li, Xiaohong Pu, Xin Yang, Yixing Yao, Junping He, Steven Y Cheng, Tingting Yu, Chen Liu, Shen Yue.

   BACKGROUND: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown.
RESULTS: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells.
CONCLUSIONS: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy.

Keywords:  AMPK; Gli1; Medulloblastoma; NF-κB; Shh signaling

DOI:  https://doi.org/10.1186/s13578-023-00963-2
Tissue Cell. 2023 Jan 22. pii: S0040-8166(23)00020-4. [Epub ahead of print]81 102032

Ellagic acid induces apoptosis and autophagy in colon cancer through the AMPK/mTOR pathway.

Xiong Ni, Fu-Sheng Shang, Ting-Feng Wang, De-Jun Wu, Da-Gui Chen, Biao Zhuang.

  Ellagic acid (EA), found in fruits and foods, has been shown to be effective in the treatment of breast, colon and bladder cancer. However, due to the complexity of colon cancer, the therapeutic mechanism of EA for colon cancer is still unclear. Cell Counting Kit-8 (CCK-8) assay were employed to investigate the cell proliferation. Western blotting and flow cytometry assays were utilized to investigate apoptosis and autophagy in CRC cells (HCT116), respectively. Moreover, western blotting and luciferase reporter assays were evaluated the effect of EA on AMPK/mTOR pathway. Through flow cytometry analysis, EA could promote the apoptosis of HCT116 cells. In addition, EA can reduce the phosphorylation of mTOR, promoted phosphorylation of AMPK, and induced autophagy in HCT116 cells. Also, Dorsomorphin pretreatment can reduce the expression of autophagy protein, which indicates that EA induces autophagy through AMPK/mTOR pathway. These results suggest that EA inhibits the growth of colon cancer through AMPK/mTOR pathway and induces apoptosis and protective autophagy.

Keywords:  AMPK/mTOR; Apoptosis; Autophagy; Colon cancer; Ellagic acid

DOI:  https://doi.org/10.1016/j.tice.2023.102032
Cell Death Discov. 2023 Jan 21. 9(1): 16

Resveratrol protects osteocytes against oxidative stress in ovariectomized rats through AMPK/JNK1-dependent pathway leading to promotion of autophagy and inhibition of apoptosis.

Liwei Wei, Shuang Chai, Chen Yue, Hong Zhang, Jitian Li, Na Qin.

A large number of studies in recent years indicate that osteocytes are the orchestrators of bone remodeling by regulating both osteoblast and osteoclast activities. Oxidative stress-induced osteocyte apoptosis plays critical roles in the pathological processes of postmenopausal osteoporosis. Resveratrol is a natural polyphenolic compound that ameliorates postmenopausal osteoporosis. However, whether resveratrol regulates osteocyte apoptosis via autophagy remains largely unknown. The effects of resveratrol on regulating osteocyte apoptosis and autophagy were analyzed both in vivo and in vitro. In vitro, cultured MLO-Y4 cells were exposed to H2O2 with or without resveratrol. In vivo, an ovariectomy-induced osteoporosis model was constructed in rats with or without daily intraperitoneal injection of 10 mg/kg body weight resveratrol. It was found that resveratrol attenuated H2O2-induced apoptosis through activating autophagy in cultured MLO-Y4 cells, which was mediated by the dissociation of Beclin-1/Bcl-2 complex in AMPK/JNK1-dependent pathway, ultimately regulating osteocytes function. Furthermore, it was shown that resveratrol treatment reduced osteocytes oxidative stress, inhibited osteocytes apoptosis and promoted autophagy in ovariectomized rats. Our study suggests that resveratrol protects against oxidative stress by restoring osteocytes autophagy and alleviating apoptosis via AMPK/JNK1 activation, therefore dissociating Bcl-2 from Beclin-1.

DOI: https://doi.org/10.1038/s41420-023-01331-2