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The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

ABSTRACT: The activity of 5’-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we have screened for inhibitors that prevent FBP from binding to aldolase, and have identified Aldometanib that prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, Aldometanib elicits an insulin-independent glucose lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis (NASH) in obese male rodents. Moreover, Aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, Aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

ORGANISM(S): Oryctolagus Cuniculus

SUBMITTER: Shengcai Lin

PROVIDER: PXD035968 | iProX | Wed Aug 10 00:00:00 BST 2022

REPOSITORIES: iProX

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The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.

Zhang Chen-Song CS Li Mengqi M Wang Yu Y Li Xiaoyang X Zong Yue Y Long Shating S Zhang Mingliang M Feng Jin-Wei JW Wei Xiaoyan X Liu Yan-Hui YH Zhang Baoding B Wu Jianfeng J Zhang Cixiong C Lian Wenhua W Ma Teng T Tian Xiao X Qu Qi Q Yu Yaxin Y Xiong Jinye J Liu Dong-Tai DT Wu Zhenhua Z Zhu Mingxia M Xie Changchuan C Wu Yaying Y Xu Zheni Z Yang Chunyan C Chen Junjie J Huang Guohong G He Qingxia Q Huang Xi X Zhang Lei L Sun Xiufeng X Liu Qingfeng Q Ghafoor Abdul A Gui Fu F Zheng Kaili K Wang Wen W Wang Zhi-Chao ZC Yu Yong Y Zhao Qingliang Q Lin Shu-Yong SY Wang Zhi-Xin ZX Piao Hai-Long HL Deng Xianming X Lin Sheng-Cai SC

Nature metabolism 20221010 10

The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify al ...[more]

PMID: 36217034

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Project description:Glioblastoma, the most frequent primary malignant brain tumor in adults, is characterized by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumor cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. We have previously shown that the peroxisome proliferator–activated receptor γ coactivator (PGC)-1α is a key regulator of cellular respiration, proliferation and invasion in glioblastoma. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (PGC-1α stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of adenosine monophosphate kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity towards non-glucose nutrients including galactose, fatty acids and ketone bodies. Moreover, spatially resolved multi-omic analysis integrating transcriptomics and matrix-assisted laser desorption/ionization (MALDI) was used to correlate the gene expression pattern of PGC-1α with local metabolic and genetic architecture in human glioblastoma tissue sections. A nutrient switch from glucose to galactose, ketone bodies or fatty acids triggered an initial activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs towards mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under non-glucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with non-hypoxic tumor niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs which result in upregulation of the enzymatic machinery necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data from human glioblastoma samples confirms the relevance of PGC-1α especially in non-hypoxic tumor regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.

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The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

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The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.

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