Mitochondrial dysfunction induces radioresistance in colorectal cancer by activating [Ca 2+ ] m -PDP1-PDH-histone acetylation retrograde signaling

• Published in: Cell death & disease Vol. 12; no. 9; p. 837
• Main Authors: Shi, Yingying, Wang, You, Jiang, Huangang, Sun, Xuehua, Xu, Hui, Wei, Xue, Wei, Yan, Xiao, Guohui, Song, Zhiyin, Zhou, Fuxiang
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 06.09.2021; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Acetylation; Adenosine Triphosphate - metabolism; Animals; Apoptosis; Calcium - metabolism; Calcium signalling; Cancer; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cytoplasm; Disease-Free Survival; DNA Damage; DNA Repair; Down-Regulation - genetics; Electron transport chain; Female; Gene Expression Regulation, Neoplastic; Glycolysis; Histones; Histones - metabolism; Humans; Kaplan-Meier Estimate; Male; Mice; Mice, Nude; Middle Aged; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; NADH Dehydrogenase - metabolism; NADH-ubiquinone oxidoreductase; Protein Phosphatase 2C - metabolism; Pyruvate Dehydrogenase Complex - metabolism; Pyruvic acid; Radiation therapy; Radiation Tolerance; Radioresistance; Radiosensitivity; Retrograde transport; Rotenone - pharmacology; Signal Transduction; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03984-2

Mitochondrial retrograde signaling (mito-RTG) triggered by mitochondrial dysfunction plays a potential role in regulating tumor metabolic reprogramming and cellular sensitivity to radiation. Our previous studies showed phos-pyruvate dehydrogenase (p-PDH) and PDK1, which involved in aerobic glycolysis, were positively correlated with radioresistance, but how they initiate and work in the mito-RTG pathway is still unknown. Our further genomics analysis revealed that complex I components were widely downregulated in mitochondrial dysfunction model. In the present study, high expression of p-PDH was found in the complex I deficient cells and induced radioresistance. Mechanistically, complex I defects led to a decreased PDH both in cytoplasm and nucleus through [Ca ] -PDP1-PDH axis, and decreased PDH in nucleus promote DNA damage repair (DDR) response via reducing histone acetylation. Meanwhile, NDUFS1 (an important component of the complex I) overexpression could enhance the complex I activity, reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro. Furthermore, low NDUFS1 and PDH expression were validated to be correlated with poor tumor regression grading (TRG) in local advanced colorectal cancer (CRC) patients underwent neoadjuvant radiotherapy. Here, we propose that the [Ca ] -PDP1-PDH-histone acetylation retrograde signaling activated by mitochondrial complex I defects contribute to cancer cell radioresistance, which provides new insight in the understanding of the mito-RTG. For the first time, we reveal that NDUFS1 could be served as a promising predictor of radiosensitivity and modification of complex I function may improve clinical benefits of radiotherapy in CRC.