Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
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低剂量二甲双胍通过 PEN2 靶向溶酶体 AMPK 通路
DOI：
10.1038/s41586-022-04431-8
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Lin SC
中科院分区：
文献类型：
--
作者：
Ma T;Tian X;Zhang B;Li M;Wang Y;Yang C;Wu J;Wei X;Qu Q;Yu Y;Long S;Feng JW;Li C;Zhang C;Xie C;Wu Y;Xu Z;Chen J;Yu Y;Huang X;He Y;Yao L;Zhang L;Zhu M;Wang W;Wang ZC;Zhang M;Bao Y;Jia W;Lin SY;Ye Z;Piao HL;Deng X;Zhang CS;Lin SC
二甲双胍是最常用的抗糖尿病药物，已显示出其他益处，如抗衰老和抗癌作用。对于二甲双胍的临床剂量，AMP活化蛋白激酶（AMPK）在其作用机制中起主要作用;然而，二甲双胍的直接分子靶点仍然未知。在这里，我们表明临床相关浓度的二甲双胍抑制溶酶体质子泵v-ATP酶，这是葡萄糖饥饿后AMPK激活的中心节点。我们合成了一种光敏二甲双胍探针，并鉴定了PEN2（γ-分泌酶的一个亚基）作为二甲双胍的结合伴侣，其解离常数为微摩尔水平。二甲双胍结合的PEN2与ATP 6AP 1（v-ATP酶的亚基）形成复合物，其导致v-ATP酶的抑制和AMPK的活化，而不影响细胞AMP水平。敲除PEN2或重新引入不结合ATP 6AP 1的PEN2突变体会减弱AMPK活化。在体内，Pen2的肝脏特异性敲除消除了二甲双胍介导的肝脂肪含量的降低，而Pen2的精氨酸特异性敲除削弱了其降糖作用。此外，敲低秀丽隐杆线虫中的pen-2消除了二甲双胍诱导的寿命延长。总之，这些发现揭示了二甲双胍结合PEN2并启动信号传导途径，该途径通过ATP 6AP 1与AMPK活化的溶酶体葡萄糖敏感途径相交。这确保了二甲双胍在患者中发挥其治疗益处，而没有实质性的不良反应。抗糖尿病药物二甲双胍的分子靶点被鉴定为PEN 2，这是γ-分泌酶的一个亚基，PEN 2-ATP 6AP 1轴为筛选二甲双胍替代品提供了潜在的靶点。
Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects. The molecular target of the antidiabetic medicine metformin is identified as PEN2, a subunit of γ-secretases, and the PEN2–ATP6AP1 axis offers potential targets for screening for metformin substitutes.
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影响因子：
48
作者：
Dempsey, Graham T.;Vaughan, Joshua C.;Chen, Kok Hao;Bates, Mark;Zhuang, Xiaowei
通讯作者：
Zhuang, Xiaowei
影响因子：
29
作者：
Howell JJ;Hellberg K;Turner M;Talbott G;Kolar MJ;Ross DS;Hoxhaj G;Saghatelian A;Shaw RJ;Manning BD
通讯作者：
Manning BD
影响因子：
9.8
作者：
Fu, Lizhi;Bruckbauer, Antje;Xue, Bingzhong
通讯作者：
Xue, Bingzhong
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
16.2
作者：
Lalau, Jean-Daniel;Kajbaf, Farshad;De Broe, Marc E.
通讯作者：
De Broe, Marc E.