bims-amsmem 2023-05-28 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–05–28
eight papers selected by
Dipsikha Biswas, Københavns Universitet

Redefining the role of AMPK in autophagy and the energy stress response.
AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.
Roflumilast reduces myocardial ischemia reperfusion injury in vivo and in vitro by activating the AMPK signaling pathway.
Loss of AMPKα2 promotes melanoma tumor growth and brain metastasis.
Inhibition of NADPH Oxidase (NOX) 2 Mitigates Colitis in Mice with Impaired Macrophage AMPK Function.
MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.
Obesity wars: hypothalamic sEVs a new hope.
Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress.

Nat Commun. 2023 May 24. 14(1): 2994

Redefining the role of AMPK in autophagy and the energy stress response.

Ji-Man Park, Da-Hye Lee, Do-Hyung Kim.

Autophagy maintains cellular homeostasis during low energy states. According to the current understanding, glucose-depleted cells induce autophagy through AMPK, the primary energy-sensing kinase, to acquire energy for survival. However, contrary to the prevailing concept, our study demonstrates that AMPK inhibits ULK1, the kinase responsible for autophagy initiation, thereby suppressing autophagy. We found that glucose starvation suppresses amino acid starvation-induced stimulation of ULK1-Atg14-Vps34 signaling via AMPK activation. During an energy crisis caused by mitochondrial dysfunction, the LKB1-AMPK axis inhibits ULK1 activation and autophagy induction, even under amino acid starvation. Despite its inhibitory effect, AMPK protects the ULK1-associated autophagy machinery from caspase-mediated degradation during energy deficiency, preserving the cellular ability to initiate autophagy and restore homeostasis once the stress subsides. Our findings reveal that dual functions of AMPK, restraining abrupt induction of autophagy upon energy shortage while preserving essential autophagy components, are crucial to maintain cellular homeostasis and survival during energy stress.

DOI: https://doi.org/10.1038/s41467-023-38401-z
Nat Commun. 2023 May 22. 14(1): 2740

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.

Eva Crosas-Molist, Vittoria Graziani, Oscar Maiques, Pahini Pandya, Joanne Monger, Remi Samain, Samantha L George, Saba Malik, Jerrine Salise, Valle Morales, Adrien Le Guennec, R Andrew Atkinson, Rosa M Marti, Xavier Matias-Guiu, Guillaume Charras, Maria R Conte, Alberto Elosegui-Artola, Mark Holt, Victoria Sanz-Moreno.

Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

DOI: https://doi.org/10.1038/s41467-023-38292-0
Exp Ther Med. 2023 Jun;25(6): 302

Roflumilast reduces myocardial ischemia reperfusion injury in vivo and in vitro by activating the AMPK signaling pathway.

Bo Liao, Zhongyuan Han.

  Myocardial tissue cell damage induced by myocardial ischemia/reperfusion (MI/R) notably elevates the mortality rate, increases the complications of patients with myocardial infarction and decreases reperfusion benefit in patients suffering from acute myocardial infarction. Roflumilast protect against cardiotoxicity. Therefore, the present study aimed to investigate the effect of roflumilast on MI/R injury and the underlying mechanisms. To simulate MI/R in vivo and in vitro, the rat model of MI/R was established and H9C2 cells were subjected to hypoxia/reoxygenation (H/R) induction, respectively. The myocardial infarction areas were observed by 2,3,5-triphenyltetrazolium chloride staining. The myocardial enzyme levels in serum and levels of inflammatory cytokines and oxidative stress markers in cardiac tissue were assessed by corresponding assay kits. The cardiac damage was observed by hematoxylin and eosin staining. The mitochondrial membrane potential in cardiac tissue and H9C2 cells was detected using the JC-1 staining kit. The viability and apoptosis of H9C2 cells were detected by Cell Counting Kit-8 and TUNEL assay, respectively. The levels of inflammatory cytokines, oxidative stress markers and ATP in H/R-induced H9C2 cells were analyzed by corresponding assay kits. Western blotting was used for the estimation of AMP-activated protein kinase (AMPK) signaling pathway-, apoptosis- and mitochondrial regulation-associated protein levels. The mPTP opening was detected using a calcein-loading/cobalt chloride-quenching system. The results indicated that roflumilast decreased MI/R-induced myocardial infarction by alleviating myocardial injury and mitochondrial damage through the activation of the AMPK signaling pathway. In addition, roflumilast mitigated viability damage, alleviated oxidative stress, attenuated the inflammatory response and decreased mitochondrial damage in H/R-induced H9C2 cells by activating the AMPK signaling pathway. However, compound C, an inhibitor of the AMPK signaling pathway, reversed the effect of roflumilast on H/R-induced H9C2 cells. In conclusion, roflumilast alleviated myocardial infarction in MI/R rats and attenuated H/R-induced oxidative stress, inflammatory response and mitochondrial damage in H9C2 cells by activating the AMPK signaling pathway.

Keywords:  AMP-activated protein kinase signaling pathway; mitochondrial damage; myocardial ischemia reperfusion injury; roflumilast

DOI:  https://doi.org/10.3892/etm.2023.12001
iScience. 2023 Jun 16. 26(6): 106791

Loss of AMPKα2 promotes melanoma tumor growth and brain metastasis.

Ping Yuan, Da Teng, Evelyn de Groot, Man Li, Sebastian Trousil, Che-Hung Shen, Jason Roszik, Michael A Davies, Y N Vashisht Gopal, Bin Zheng.

  AMP-activated protein kinase (AMPK) is a critical cellular energy sensor at the interface of metabolism and cancer. However, the role of AMPK in carcinogenesis remains unclear. Here, through analysis of the TCGA melanoma dataset, we found that PRKAA2 gene that encodes the α2 subunit of AMPK is mutated in ∼9% of cutaneous melanomas, and these mutations tend to co-occur with NF1 mutations. Knockout of AMPKα2 promoted anchorage-independent growth of NF1-mutant melanoma cells, whereas ectopic expression of AMPKα2 inhibited their growth in soft agar assays. Moreover, loss of AMPKα2 accelerated tumor growth of NF1-mutant melanoma and enhanced their brain metastasis in immune-deficient mice. Our findings support that AMPKα2 serves as a tumor suppressor in NF1-mutant melanoma and suggest that AMPK could be a therapeutic target for treating melanoma brain metastasis.

Keywords:  Biological database; Cancer; Molecular Genetics

DOI:  https://doi.org/10.1016/j.isci.2023.106791
Biomedicines. 2023 May 14. pii: 1443. [Epub ahead of print]11(5):

Inhibition of NADPH Oxidase (NOX) 2 Mitigates Colitis in Mice with Impaired Macrophage AMPK Function.

Suhrid Banskota, Huaqing Wang, Yun Han Kwon, Jaya Gautam, Sabah Haq, Jensine Grondin, Gregory R Steinberg, Waliul I Khan.

  Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion in macrophages during inflammation, while increased NOX2 expression is reported in experimental models of colitis and inflammatory bowel disease (IBD) patients. Although there are reductions in AMPK activity in IBD, it remains unclear whether targeted inhibition of NOX2 in the presence of defective AMPK can reduce the severity of colitis. Here, we investigate whether the inhibition of NOX2 ameliorates colitis in mice independent of AMPK activation. Our study identified that VAS2870 (a pan-Nox inhibitor) alleviated dextran sodium sulfate (DSS)-induced colitis in macrophage-specific AMPKβ1-deficient (AMPKβ1LysM) mice. Additionally, VAS2870 blocked LPS-induced TLR-4 and NOX2 expression, ROS production, nuclear translocation of NF-κB, and pro-inflammatory cytokine secretion in bone marrow-derived macrophages (BMDMs) from AMPKβ1LysM mice, whereas sodium salicylate (SS; AMPK β1 activator) did not. Both VAS2870 and SS inhibited LPS-induced NOX2 expression, ROS production, and pro-inflammatory cytokine secretions in bone marrow-derived macrophages (BMDMs) from wildtype (AMPKβ1fl/fl) mice but only VAS2870 inhibited these effects of LPSs in AMPKβ1LysM BMDMs. Furthermore, in macrophage cells (RAW 264.7), both SS and VAS2870 inhibited ROS production and the secretion of pro-inflammatory cytokines and reversed the impaired autophagy induced by LPSs. These data suggest that inhibiting NOX2 can reduce inflammation independent of AMPK in colitis.

Keywords:  AMPK; NOX2; autophagy; colitis; inflammation; macrophages

DOI:  https://doi.org/10.3390/biomedicines11051443
Life Sci Alliance. 2023 08;pii: e202201525. [Epub ahead of print]6(8):

MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.

Mary Rose Branch, Cynthia L Hsu, Kohta Ohnishi, Wen-Chuan Shen, Elian Lee, Jill Meisenhelder, Brett Winborn, Bryce L Sopher, J Paul Taylor, Tony Hunter, Albert R La Spada.

mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.

DOI: https://doi.org/10.26508/lsa.202201525
Trends Mol Med. 2023 May 18. pii: S1471-4914(23)00088-6. [Epub ahead of print]

Obesity wars: hypothalamic sEVs a new hope.

Sayani Mukherjee, Carlos Diéguez, Johan Fernø, Miguel López.

  There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

Keywords:  AMPK; GLP-1; food intake; hypothalamus; obesity; small extracellular vesicles; thermogenesis

DOI:  https://doi.org/10.1016/j.molmed.2023.04.006
Eur J Nutr. 2023 May 23.

Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress.

Yaowei Bai, Tongqiang Li, Jiacheng Liu, Yingliang Wang, Chaoyang Wang, Shuguang Ju, Chen Zhou, Yang Chen, Wei Yao, Bin Xiong.

   BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease. We explored simple and effective ways to improve NAFLD and investigate the mechanism of action.
METHODS: NAFLD was induced in 40 rats fed a high-fat diet (HFD). Magnetic resonance imaging was used to evaluate the progression and improvement of NAFLD. The treatment-related interventions included aerobic exercise (E) and vitamin E (VE) supplementation. Expression levels of proteins related to fat metabolism were also assessed. The activities of antioxidant enzymes in the liver and serum lipid metabolism were analyzed using biochemical methods.
RESULTS: Aerobic exercise and vitamin E effectively improved NAFLD in rats, resulting in decreased hepatic fat accumulation, reduced hepatocyte ballooning, and decreased triglyceride levels. Combination therapy achieved the best effect. Both aerobic exercise and vitamin E activate the AMPK pathway to phosphorylate acetyl-CoA carboxylase (ACC) and reduce fatty acid synthesis. The expression of sterol regulatory element-binding protein-1 (SREBP-1) was decreased significantly in the treated groups, particularly in the E + VE + HFD group. The expression of carnitine palmitoyl-transferase 1C (CPT1C) significantly increased in the treated groups, particularly in the E + VE + HFD group. Compared with the control group, reactive oxygen species (ROS) in the E + HFD group were slightly decreased, while that in the VE + HFD group were significantly decreased, with the even greater reduction observed in the E + VE + HFD group.
CONCLUSION: Aerobic exercise and vitamin E supplementation can improve HFD-induced NAFLD in rats by regulating the AMPK pathway and reducing oxidative stress.

Keywords:  Aerobic exercise; Antioxidants; Fat metabolism; NAFLD

DOI:  https://doi.org/10.1007/s00394-023-03179-9