HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia

Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, imm...

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Bibliographic Details
Published in:	Cell death & disease Vol. 15; no. 2; p. 155
Main Authors:	Jing, Mengjia, Xiong, Xiaofeng, Mao, Xin, Song, Qianben, Zhang, Lumiao, Ouyang, Yiming, Pang, Yingzhi, Fu, Yu, Yan, Wei
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 20-02-2024 Springer Nature B.V Nature Publishing Group
Subjects:	13 14/28 14/34 14/35 14/63 631/67/322 631/67/327 82/29 82/58 Antibodies Biochemistry Bioinformatics Biomedical and Life Sciences Carcinoma, Hepatocellular - pathology Carrier Proteins - metabolism Cell Biology Cell Culture Cell Line, Tumor Cell membranes Chromatin Flow cytometry Gene Expression Regulation, Neoplastic Hepatocellular carcinoma HMGB1 protein HMGB1 Protein - genetics HMGB1 Protein - metabolism Humans Hypoxia Hypoxia - genetics Immunofluorescence Immunology Immunoprecipitation Invasiveness Life Sciences Liver cancer Liver Neoplasms - pathology Metastases Mitochondria Mitochondria - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Nanotubes Protein transport Proteins rac1 GTP-Binding Protein - genetics rac1 GTP-Binding Protein - metabolism Rac1 protein rho GTP-Binding Proteins - metabolism Scanning electron microscopy
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Summary:	Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, immunofluorescence, and flow cytometry were used to detect the mitochondrial transfer between HCC cells. We found that mitochondrial transfer between HCC cells was confirmed using tunnel nanotubes (TNTs). The transfer of mitochondria from the highly invasive HCC cells to the less invasive HCC cells could enhance the migration and invasion ability of the latter. The hypoxic conditions increased the mitochondrial transfer between HCC cells. Then the mechanism was identified using co-immunoprecipitation, luciferase reporter assay, and chromatin immunoprecipitation. We found that RHOT1, a mitochondrial transport protein, promoted mitochondrial transfer and the migration and metastasis of HCC cells during this process. Under hypoxia, HMGB1 further regulated RHOT1 expression by increasing the expression of NFYA and NFYC subunits of the NF-Y complex. RAC1, a protein associated with TNTs formation, promoted mitochondrial transfer and HCC development. Besides, HMGB1 regulated RAC1 aggregation to the cell membrane under hypoxia. Finally, the changes and significance of related molecules in clinical samples of HCC were analyzed using bioinformatics and tissue microarray analyses. We found that HCC patients with high HMGB1, RHOT1, or RAC1 expression exhibited a relatively shorter overall survival period. In conclusion, under hypoxic conditions, HMGB1 promoted mitochondrial transfer and migration and invasion of HCC cells by increasing the expression of mitochondrial transport protein RHOT1 and TNTs formation-related protein RAC1.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-024-06536-6