Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2

Abstract 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...

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Autores principales:	Chenyang Duan, Lei Kuang, Chen Hong, Xinming Xiang, Jiancang Liu, Qinghui Li, Xiaoyong Peng, Yuanqun Zhou, Hongchen Wang, Liangming Liu, Tao Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/733592f56057452da39d25b764879fe3
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spelling	oai:doaj.org-article:733592f56057452da39d25b764879fe32021-11-07T12:05:18ZMitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK210.1038/s41419-021-04343-x2041-4889https://doaj.org/article/733592f56057452da39d25b764879fe32021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04343-xhttps://doaj.org/toc/2041-4889Abstract 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.Chenyang DuanLei KuangChen HongXinming XiangJiancang LiuQinghui LiXiaoyong PengYuanqun ZhouHongchen WangLiangming LiuTao LiNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Chenyang Duan Lei Kuang Chen Hong Xinming Xiang Jiancang Liu Qinghui Li Xiaoyong Peng Yuanqun Zhou Hongchen Wang Liangming Liu Tao Li Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
description	Abstract 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.
format	article
author	Chenyang Duan Lei Kuang Chen Hong Xinming Xiang Jiancang Liu Qinghui Li Xiaoyong Peng Yuanqun Zhou Hongchen Wang Liangming Liu Tao Li
author_facet	Chenyang Duan Lei Kuang Chen Hong Xinming Xiang Jiancang Liu Qinghui Li Xiaoyong Peng Yuanqun Zhou Hongchen Wang Liangming Liu Tao Li
author_sort	Chenyang Duan
title	Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
title_short	Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
title_full	Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
title_fullStr	Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
title_full_unstemmed	Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2
title_sort	mitochondrial drp1 recognizes and induces excessive mptp opening after hypoxia through bax-pic and lrrk2-hk2
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/733592f56057452da39d25b764879fe3
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Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2

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