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

The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

  • Nat Metab. 2022 Oct 10. doi: 10.1038/s42255-022-00640-7.
Chen-Song Zhang # 1,  Mengqi Li # 1,  Yu Wang # 1,  Xiaoyang Li # 1,  Yue Zong # 1,  Shating Long 1,  Mingliang Zhang 2,  Jin-Wei Feng 1,  Xiaoyan Wei 1,  Yan-Hui Liu 1,  Baoding Zhang 1,  Jianfeng Wu 3,  Cixiong Zhang 1,  Wenhua Lian 1,  Teng Ma 1,  Xiao Tian 1,  Qi Qu 1,  Yaxin Yu 1,  Jinye Xiong 1,  Dong-Tai Liu 1,  Zhenhua Wu 1,  Mingxia Zhu 1,  Changchuan Xie 1,  Yaying Wu 1,  Zheni Xu 1,  Chunyan Yang 1,  Junjie Chen 4,  Guohong Huang 1,  Qingxia He 5,  Xi Huang 1,  Lei Zhang 1,  Xiufeng Sun 1,  Qingfeng Liu 1,  Abdul Ghafoor 1,  Fu Gui 1,  Kaili Zheng 6,  Wen Wang 7,  Zhi-Chao Wang 7,  Yong Yu 1,  Qingliang Zhao 6,  Shu-Yong Lin 1,  Zhi-Xin Wang 5,  Hai-Long Piao 7,  Xianming Deng 8,  Sheng-Cai Lin 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian, China.
  • 2 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 3 Laboratory Animal Research Centre, Xiamen University, Fujian, China.
  • 4 Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University, Fujian, China.
  • 5 Key Laboratory of Ministry of Education for Protein Science, School of Life Sciences, Tsinghua University, Beijing, China.
  • 6 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Fujian, China.
  • 7 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, China.
  • 8 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian, China. xmdeng@xmu.edu.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian, China. linsc@xmu.edu.cn.
  • # Contributed equally.
PMID: 36217034 DOI: 10.1038/s42255-022-00640-7
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 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 aldometanib in a screen for aldolase inhibitors and show that it 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 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.

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