HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region
Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651322009253 |
| _version_ | 1798000569160302592 |
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| author | Shibo Bao Cong Zhang Shengxiang Luo Liping Jiang Qiujuan Li Ying Kong Jun Cao |
| author_facet | Shibo Bao Cong Zhang Shengxiang Luo Liping Jiang Qiujuan Li Ying Kong Jun Cao |
| author_sort | Shibo Bao |
| collection | DOAJ |
| description | Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in A549 and HELF cells. First, knockdown of HMGA2 by siHMGA2 significantly attenuated Cr (VI)-reduced expression of OXPHOS-related proteins (COX IV and ND1) and mitochondrial mass, indicating that HMGA2 was involved in Cr (VI)-reduced OXPHOS. Overexpression of HMGA2 by transfection of HMGA2-DNA plasmids reduced the expression of COX IV, ND1 and mitochondrial mass, suggesting the negative role of HMGA2 in OXPHOS. Secondly, both CCCP, the inhibitor of mitochondrial function, and the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), decreased the level of HMGA2, indicating that the interaction of mitochondrial dysfunction and ER stress resulted in Cr (VI)-induced HMGA2 expression. Further study demonstrated that ER stress/HMGA2 axis mediated the metabolism rewiring from OXPHOS to aerobic glycolysis. Notably, Cr (VI) induced the accumulation of HMGA2 proteins in mitochondria and ChIP assay demonstrated that HMGA2 proteins could bind to D-loop region of mitochondrial DNA (mtDNA), which provided the proof for HMGA2-modulating OXPHOS. Taken together, our results suggested that the interaction of mitochondria and ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis by binding directly to D-loop region of mtDNA. This work informs on the potential mode of action for Cr (VI)-induced tumors and builds on growing evidence regarding the contribution of cellular metabolic disruption contributing to carcinogenicity. |
| first_indexed | 2024-04-11T11:22:24Z |
| format | Article |
| id | doaj.art-268a34b255434da38ee4a64181141261 |
| institution | Directory Open Access Journal |
| issn | 0147-6513 |
| language | English |
| last_indexed | 2024-04-11T11:22:24Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj.art-268a34b255434da38ee4a641811412612022-12-22T04:26:35ZengElsevierEcotoxicology and Environmental Safety0147-65132022-10-01244114085HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop regionShibo Bao0Cong Zhang1Shengxiang Luo2Liping Jiang3Qiujuan Li4Ying Kong5Jun Cao6Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, ChinaDepartment of Food Nutrition and Safety, Dalian Medical University, Dalian 116044, ChinaDepartment of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, ChinaDepartment of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, ChinaDepartment of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, ChinaDepartment of Biochemistry and Molecular Biology, Dalian Medical University, Dalian 116044, ChinaDepartment of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian 116044, China; Correspondence to: Occupational and Environmental Health Department, Dalian Medical University, Dalian 116044, China.Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in A549 and HELF cells. First, knockdown of HMGA2 by siHMGA2 significantly attenuated Cr (VI)-reduced expression of OXPHOS-related proteins (COX IV and ND1) and mitochondrial mass, indicating that HMGA2 was involved in Cr (VI)-reduced OXPHOS. Overexpression of HMGA2 by transfection of HMGA2-DNA plasmids reduced the expression of COX IV, ND1 and mitochondrial mass, suggesting the negative role of HMGA2 in OXPHOS. Secondly, both CCCP, the inhibitor of mitochondrial function, and the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), decreased the level of HMGA2, indicating that the interaction of mitochondrial dysfunction and ER stress resulted in Cr (VI)-induced HMGA2 expression. Further study demonstrated that ER stress/HMGA2 axis mediated the metabolism rewiring from OXPHOS to aerobic glycolysis. Notably, Cr (VI) induced the accumulation of HMGA2 proteins in mitochondria and ChIP assay demonstrated that HMGA2 proteins could bind to D-loop region of mitochondrial DNA (mtDNA), which provided the proof for HMGA2-modulating OXPHOS. Taken together, our results suggested that the interaction of mitochondria and ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis by binding directly to D-loop region of mtDNA. This work informs on the potential mode of action for Cr (VI)-induced tumors and builds on growing evidence regarding the contribution of cellular metabolic disruption contributing to carcinogenicity.http://www.sciencedirect.com/science/article/pii/S0147651322009253Potassium dichromateHMGA2GlycolysisOxidative phosphorylationER stress |
| spellingShingle | Shibo Bao Cong Zhang Shengxiang Luo Liping Jiang Qiujuan Li Ying Kong Jun Cao HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region Ecotoxicology and Environmental Safety Potassium dichromate HMGA2 Glycolysis Oxidative phosphorylation ER stress |
| title | HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region |
| title_full | HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region |
| title_fullStr | HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region |
| title_full_unstemmed | HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region |
| title_short | HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region |
| title_sort | hmga2 mediates cr vi induced metabolic reprogramming through binding to mitochondrial d loop region |
| topic | Potassium dichromate HMGA2 Glycolysis Oxidative phosphorylation ER stress |
| url | http://www.sciencedirect.com/science/article/pii/S0147651322009253 |
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