Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK
Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK
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瞬时受体电位 V 通道对于醛缩酶和 AMPK 的葡萄糖传感至关重要
DOI：
10.1016/j.cmet.2019.05.018
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发表时间：
2019-09-03
期刊：
影响因子：
29
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Li, Mengqi;Zhang, Chen-Song;Lin, Sheng-Cai
果糖-1，6-二磷酸(FBP)醛缩酶通过溶酶体途径将葡萄糖供应减少与AMPK激活联系起来。然而，醛缩酶如何将FBP缺乏占位传递到AMPK激活仍不清楚。在这里，我们证明了FBP未被占据的醛缩酶与内质网(ER)定位的瞬时受体电位通道亚家族V相互作用并抑制，从而抑制低糖中的钙释放。内质网和溶酶体之间接触部位的钙离子减少使得被抑制的TRPV可与溶酶体v-ATPase结合，然后招募Axin：LKB1独立于AMP激活AMPK。TRPVs的基因缺失阻止了葡萄糖饥饿诱导的小鼠细胞和肝脏以及线虫中AMPK的激活，这表明了TRPVs的生理需求。药物抑制TRPV可激活AMPK并提高衰老肌肉中的NAD(+)水平，从而恢复动物的跑步能力。我们的研究表明，TRPVs将醛缩酶的无FBP状态传递给v-ATPase的重新配置，导致低糖条件下AMPK的激活。
Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD(+) levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.