AMPK信号通道调节自噬和线粒体稳态的研究进展

Research progress in the regulation of autophagy and mitochondrial homeostasis by AMPK signaling channels

AMP活化蛋白激酶(AMPK)是一种广泛存在于真核细胞生物中且进化上保守的丝氨酸/苏氨酸蛋白激酶。在调控细胞能量代谢方面,AMPK作为能量代谢激酶具有极其重要的作用。当机体处于低能量状态时,AMPK对细胞内腺嘌呤核苷酸水平的变化作出反应,与一磷酸腺苷(AMP)或二磷酸腺苷(ADP)结合后被激活。激活的AMPK可调控各种代谢过程,包括脂质、葡萄糖代谢和细胞自噬。AMPK可通过磷酸化哺乳动物雷帕霉素靶蛋白复合物1(mTORC1)、丝氨酸/苏氨酸蛋白激酶-失调51样激酶1(ULK1)和Ⅲ型磷脂酰肌醇3-激酶-空泡分选蛋白34(PIK3C3-VPS34)复合物中的自噬相关蛋白直接促进细胞自噬;也可通过调节叉头框蛋白O3(FOXO3)、溶酶体功能的转录因子EB(TFEB)和溴结构域蛋白4(BRD4)等转录因子下游自噬相关基因的表达间接促进细胞自噬;还可调节线粒体自噬,诱导受损的线粒体分裂,促进自噬反应向受损线粒体转移。AMPK另一个功能是调控线粒体健康,可通过刺激线粒体生物发生参与并调控线粒体内稳态的各个方面。本综述讨论了AMPK信号通道作为细胞响应能量应激和调控线粒体的中心,对线粒体生物学和内环境稳态的重要调控作用,重点介绍了AMPK在调节细胞自噬和线粒体自噬过程中的关键作用,以及调控线粒体稳态的研究进展。

AMP-activated protein kinase(AMPK)is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells.In regulating cellular energy metabolism,AMPK plays an extremely important role as an energy metabolic kinase.When the body is in a low energy state,AMPK is activated in response to changes in intracellular adenine nucleotide levels and is bound to adenosine monophosphate(AMP)or adenosine diphosphate(ADP).Activated AMPK regulates various metabolic processes,including lipid and glucose metabolism and cellular autophagy.AMPK directly promotes autophagy by phosphorylating autophagy-related proteins in the mammalian target of rapamycin complex 1(mTORC1),serine/threonine protein kinase-dysregulated 51-like kinase 1(ULK1)and typeⅢphosphatidylinositol 3-kinase-vacuolar protein-sorting 34(PIK3C3-VPS34)complexes.AMPK also indirectly promotes autophagy by regulating the expression of downstream autophagy-related genes of transcription factors such as forkhead box O3(FOXO3),lysosomal function transcription factor EB(TFEB)and bromodomain protein 4(BRD4).AMPK also regulates mitochondrial autophagy,induces the division of damaged mitochondria and promotes the transfer of the autophagic response to damaged mitochondria.Another function of AMPK is to regulate mitochondrial health by stimulating mitochondrial biogenesis and participating in various aspects of mitochondrial homeostasis regulation.This review discusses the specific regulation of mitochondrial biology and internal environmental homeostasis by AMPK signaling channels as central to the cellular response to energy stress and regulation of mitochondria,highlighting the key role of AMPK in regulating cellular autophagy and mitochondrial autophagy,as well as advances in research on the regulation of mitochondrial homeostasis.