Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity

doi:10.7150/thno.33100

	Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity
	Wang, Bing2 ; Wang, Zhenhua3 ; Liu, Yang1,4,5,6 ; Di, Cuixia1,4,5,6 ; Zhang, Hong1,4,5,6 ; Si, Jing1,4,5,6 ; Li, Hongyan 1,4,5,6; Wu, Qingfeng1 ; Xu, Dan1 ; Li, Ji 3
刊名	THERANOSTICS
	2019
卷号	9 期号:12 页码:3595-3607
关键词	mitochondrial transplantation NAD(+)-CD38-cADPR-Ca2+ signaling endocytosis energy metabolism radiation therapy gliomas
ISSN号	1838-7640
DOI	10.7150/thno.33100
通讯作者	Zhang, Hong(zhangh@impcas.ac.cn)
英文摘要	Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to glycolysis is a core hallmark of cancer. Alterations in cancer cell energy metabolism are linked to abnormalities in mitochondrial function. Mitochondrial dysfunction of cancer cells includes increased glycolysis, decreased apoptosis, and resistance to radiotherapy. The study was designed for two main points: firstly, to investigate whether exogenous functional mitochondria can transfer into glioma cells and explore the underlying molecular mechanisms from the perspective of endocytosis; secondly, to further verify whether the mitochondrial transplantation is able to rescue aerobic respiration, attenuate the Warburg effect and enhance the radiosensitivity of gliomas. Methods: Mitochondria were isolated from normal human astrocytes (HA) and immediately co-incubated with starved human glioma cells (U87). Confocal microscopy and gene sequencing were performed to evaluate the ability of isolated mitochondria internalization into U87 cells. The interaction between endocytosis and isolated mitochondria transfer were captured by 3D tomographic microscopy and transmission electron microscopy. NAD(+), CD38, cADPR and Ca2+ release were determined by commercial kits, western blot, HLPC-MS and Fluo-3 AM respectively. PCR array expression profiling and Seahorse XF analysis were used to evaluate the effect of mitochondrial transplantation on energy phenotypes of U87 cells. U87 cells and U87 xenografts were both treated with mitochondrial transplantation, radiation, or a combination of mitochondrial transplantation and radiation. Apoptosis in vitro and in vivo were detected by cytochrome C, cleaved caspase 9 and TUNEL staining. Results: We found that mitochondria from HA could be transferred into starved U87 cells by simple co-incubation. Starvation treatment slowed the rate of glycolysis and decreased the transformation of NAD(+) to NADH in U87 cells. A large amount of accumulated NAD(+) was released into the extracellular space. CD38 is a member of the NAD(+) glycohydrolase family that catalyzes cyclization of extracellular NAD(+) to intracellular cADPR. cADPR triggered release of Ca2+ to promote cytoskeleton remodeling and plasma membrane invagination. Thus, endocytosis involving isolated mitochondria internalization was mediated by NAD(+)-CD38-cADPR-Ca2+ signaling. Mitochondrial transfer enhanced gene and protein expression related to the tricarboxylic acid (TCA) cycle, increased aerobic respiration, attenuated glycolysis, reactivated the mitochondrial apoptotic pathway, inhibited malignant proliferation of U87 cells. Isolated mitochondria injected into U87 xenograft tumors also entered cells, and inhibited glioma growth in nude mice. Mitochondrial transplantation could enhance the radiosensitivity of gliomas in vitro and in vivo. Conclusion: These findings suggested that starvation-induced endocytosis via NAD(+)-CD38-cADPR-Ca2+ signaling could be a new mechanism of mitochondrial transplantation to rescue aerobic respiration and attenuate the Warburg effect. This mechanism could be a promising approach for radiosensitization.
资助项目	Ministry of Science and Technology National Key R D Project[SQ2018YFE020524] ; National Natural Science Foundation of China[11775280] ; CAS Light of West China Program[Y866020XB0] ; Natural Science Foundation of Gansu Province[18JR3RA391]
WOS关键词	CYCLIC ADP-RIBOSE ; MESENCHYMAL STEM-CELLS ; RYANODINE RECEPTOR ; CANCER ; INTERNALIZATION ; PROLIFERATION ; METABOLISM ; ACTIVATION ; AUTOPHAGY ; MUSCLE
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000469953000015
资助机构	Ministry of Science and Technology National Key R D Project ; National Natural Science Foundation of China ; CAS Light of West China Program ; Natural Science Foundation of Gansu Province
内容类型	期刊论文
源URL	[http://119.78.100.186/handle/113462/133482]
专题	中国科学院近代物理研究所
通讯作者	Zhang, Hong
作者单位	1.Chinese Acad Sci, Inst Modern Phys, Lanzhou, Gansu, Peoples R China 2.Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Chiba, Japan 3.Yantai Univ, Ctr Mitochondria & Hlth Ageing, Yantai, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Key Lab Heavy Ion Radiat Med Gansu Prov, Lanzhou, Gansu, Peoples R China 6.Chinese Acad Sci, Key Lab Heavy Ion Radiat Med, Lanzhou, Gansu, Peoples R China
推荐引用方式 GB/T 7714	Wang, Bing,Wang, Zhenhua,Liu, Yang,et al. Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity[J]. THERANOSTICS,2019,9(12):3595-3607.
APA	Wang, Bing.,Wang, Zhenhua.,Liu, Yang.,Di, Cuixia.,Zhang, Hong.,...&Liu, Xiongxiong.(2019).Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity.THERANOSTICS,9(12),3595-3607.
MLA	Wang, Bing,et al."Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity".THERANOSTICS 9.12(2019):3595-3607.