线粒体分裂
MPTP公司
线粒体凋亡诱导通道
线粒体通透性转换孔
品脱1
细胞生物学
DNAJA3公司
线粒体
DNM1L型
线粒体膜转运蛋白
生物
ATP-ADP转位酶
粒体自噬
线粒体融合
生物化学
线粒体DNA
线粒体内膜
细胞凋亡
程序性细胞死亡
自噬
内分泌学
多巴胺能
多巴胺
基因
作者
Chenyang Duan,Lei Kuang,Chen Hong,Xinming Xiang,Jiancang Liu,Qinghui Li,Xiaotong Peng,Yuanqun Zhou,Hongchen Wang,Liangming Liu,Tao Li
标识
DOI:10.1038/s41419-021-04343-x
摘要
Mitochondrial mass imbalance is one of the key causes of cardiovascular dysfunction after hypoxia. The activation of dynamin-related protein 1 (Drp1), as well as its mitochondrial translocation, play important roles in the changes of both mitochondrial morphology and mitochondrial functions after hypoxia. However, in addition to mediating mitochondrial fission, whether Drp1 has other regulatory roles in mitochondrial homeostasis after mitochondrial translocation is unknown. In this study, we performed a series of interaction and colocalization assays and found that, after mitochondrial translocation, Drp1 may promote the excessive opening of the mitochondrial permeability transition pore (mPTP) after hypoxia. Firstly, mitochondrial Drp1 maximumly recognizes mPTP channels by binding Bcl-2-associated X protein (BAX) and a phosphate carrier protein (PiC) in the mPTP. Then, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is recruited, whose kinase activity is inhibited by direct binding with mitochondrial Drp1 after hypoxia. Subsequently, the mPTP-related protein hexokinase 2 (HK2) is inactivated at Thr-473 and dissociates from the mitochondrial membrane, ultimately causing structural disruption and overopening of mPTP, which aggravates mitochondrial and cellular dysfunction after hypoxia. Thus, our study interprets the dual direct regulation of mitochondrial Drp1 on mitochondrial morphology and functions after hypoxia and proposes a new mitochondrial fission-independent mechanism for the role of Drp1 after its translocation in hypoxic injury.
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