AMPK targets PDZD8 to promote carbon source shift to glutamine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Shengcai Lin
PROVIDER: PXD041428 | iProX | Thu Apr 06 00:00:00 BST 2023
REPOSITORIES: iProX
Publications
AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
Li Mengqi M Wang Yu Y Wei Xiaoyan X Cai Wei-Feng WF Wu Jianfeng J Zhu Mingxia M Wang Yongliang Y Liu Yan-Hui YH Xiong Jinye J Qu Qi Q Chen Yan Y Tian Xiao X Yao Luming L Xie Renxiang R Li Xiaomin X Chen Siwei S Huang Xi X Zhang Cixiong C Xie Changchuan C Wu Yaying Y Xu Zheni Z Zhang Baoding B Jiang Bin B Wang Zhi-Chao ZC Li Qinxi Q Li Gang G Lin Shu-Yong SY Yu Li L Piao Hai-Long HL Deng Xianming X Han Jiahuai J Zhang Chen-Song CS Lin Sheng-Cai SC
Cell research 20240619 10
The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glu ...[more]
Similar Datasets
Project description:The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
| S-EPMC11442470 | biostudies-literature
Project description:Lithocholic acid (LCA), accumulated in mammals during calorie restriction (CR), can activate AMP-activated protein kinase (AMPK) and slow down ageing1. However, how LCA is signalled to activate AMPK and elicit the biological effects is unclear. Here, we show that LCA can enhance the activity of sirtuins (SIRTs) to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), thereby triggering AMPK activation via the lysosomal glucose-sensing pathway. Through proteomic analysis of SIRT1-coimmunoprecipitated proteins, we identify that TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, is an LCA receptor, and demonstrate that the LCA-bound TULP3 allosterically activates SIRTs. Activated SIRTs then deacetylate the V1E1 subunit of v-ATPase on K52, K99 and K191 residues. Muscle-specific expression of the 3KR mutant of V1E1, mimicking the deacetylated state, dominantly activates AMPK and rejuvenates muscles in aged mice. Moreover, LCA depends on the TULP3 homologues tub-1 and ktub to activate AMPK and extend lifespan and healthspan in nematodes and flies, respectively. Our study thus elucidates that LCA triggers the TULP3-sirtuin-v-ATPase-AMPK route to manifest benefits of calorie restriction. This project contains the MS data for the modification of each of 21 v-ATPase subunits and the interacting protein of SIRT1 we identified. It also contains the validation data for MEF cell lines with bile acid receptor knockout.
2024-09-16 | PXD056134 |
Project description:Deletion of AMPK significantly extended the onset of leukemogenesis and depleted leukemia initiating cells (LICs). To identify how AMPK regulates LICs, we performed gene expression profiling of LICs isolated from AMPK wild type leukemic mice or AMPK-deficient leukemic mice. 4 groups were analyzed; 1) Whole leukemia (GFP+) from AMPK WT ( AMPKfl/fl) mice, 2) Whole leukemia (GFP+) from AMPK-deficient ( AMPK?/?l) mice, 3) LICs=L-GMP (GFP+,lin-,c-kit+, CD16/32+,CD34+) cells from AMPK WT ( AMPKfl/fl) mice, 4) LICs=L-GMP (GFP+,lin-,c-kit+, CD16/32+,CD34+) cells from AMPK-deficient ( AMPK?/?l) mice.
2015-01-01 | E-GEOD-64602 | biostudies-arrayexpress
Project description:AMP-activated protein kinase (AMPK) is a major regulator of cellular energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. AMPK elicits acute and diverse metabolic effects by directly phosphorylating various targets. AMPK activation also promotes metabolic reprogramming in longer term via effects on gene expression. The aim of this study is to elucidate molecular mechanism(s) by which AMPK activation modulates metabolic adaptation through its impact on gene regulation.
2019-03-04 | GSE104170 | GEO
Project description:Inhibition of AMP-activated protein kinase (AMPK) is increasingly being explored for its therapeutic potential in some diseases, including certain types of cancers. However, AMPK-inhibitory tool compounds have largely been limited to compound C/dorsomorphin and SBI-0206965, both of which display numerous off-target effects and blocking AMPK-independent metabolic processes. Here we describe molecular insights and cellular actions/utility of a recently identified potent AMPK inhibitor BAY-3827. Sequence analysis of highly/lowly-inhibited kinases by BAY-3827, based on in vitro kinase selectivity profiling, predicted key conserved residues involved in the compound-inhibitory effect. A co-crystal structure of the AMPK kinase domain (KD)-BAY-3827 complex resolved at 2.5 Å in comparison with previously reported KD-inhibitor structures, revealed an overlapping binding site in the ATP-binding pocket and common αC helix-out conformations. We identified distinct features of BAY-3827-bound structure which involve a disulfide bridge between αD helix Cys106 and activation loop residue Cys174. This may help to stabilize AMPK conformation upon BAY-3827 binding, where the position of activation loop Asn162 leads the DFG motif Phe158 to adopt a conformation facing the C-terminal kinase lobe displacing His137, leading to a broken regulatory spine and an inactive kinase state. BAY-3827 at 2.5-5 μM, but not structurally resembling inactive BAY-974, fully blocked AMPK activator (MK-8722)-mediated phosphorylation of ACC1 and inhibition of lipogenesis in hepatocytes. Unbiased transcriptome analysis in MK-8722-treated wild-type and AMPK-null hepatocytes revealed that >30% of MK-8722-stimulated AMPK-dependent genes could be downregulated by 5 μM BAY-3827. Based on its greater selectivity and potency substantiated by comprehensive molecular/cellular investigations. BAY-3827 is a powerful tool to delineate AMPK functions.
2025-07-28 | GSE290022 | GEO
Project description:Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMPK, a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK-/- EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs over-expressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation. 2 WT and 2 AMPK DKO ESC lines were differentiated into embryoid bodies (EBs) for various lengths of time (2, 4, 8, and 12 days) in high and low glucose conditions. Both ESC and EB samples were profiled by mRNA-seq to examine how global gene expression changes associated with ESC differentiation are affected by AMPK deletion.
2016-03-09 | E-GEOD-77705 | biostudies-arrayexpress
Project description:We show activation of AMP kinase (AMPK) with single chemical compounds can endow naïve pluripotency. AMPK activators reverted early-stage differentiating cells or epi-stem cells to naïve state. Moreover, AMPK activators reverted human ESCs to naïve state with pluripotent gene expression profiles and X-chromosome reactivation.
2019-03-30 | GSE92725 | GEO
Project description:We show activation of AMP kinase (AMPK) with single chemical compounds can endow naïve pluripotency. AMPK activators reverted early-stage differentiating cells or epi-stem cells to naïve state. Moreover, AMPK activators reverted human ESCs to naïve state with pluripotent gene expression profiles and X-chromosome reactivation.
2019-03-30 | GSE92441 | GEO
Project description:Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. While AMPK, the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. In contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarisation-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
2024-11-29 | PXD056956 | Pride
Project description:We investigated the role of AMPK activation in the progression of senescence in HFDPCs. The anti-senescence effects of adenine, a recently identified AMPK activator, were determined in a comparison with AICAR, a pharmacological AMPK activator, in HFDPCs. The results showed that either adenine or AICAR induced phosphorylation of Thr172 of AMPK in HFDPCs. As revealed by microarray analysis, significant changes of gene expression pattern were observed in the high-passage HFDPCs compared with that at lower passage level. A chip study using total RNA recovered from three separate wild-type cultures of Human follicle dermal papilla cells (HFDPCs) and three separate cultures of a triple adenine-treated cells.
2014-11-01 | E-GEOD-62798 | biostudies-arrayexpress