MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium
Abstract Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd...
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202203869 |
| _version_ | 1811160430309015552 |
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| author | Cong Liu Hui‐Juan Li Wei‐Xia Duan Yu Duan Qin Yu Tian Zhang Ya‐Pei Sun Yuan‐Yuan Li Yong‐Sheng Liu Shang‐Cheng Xu |
| author_facet | Cong Liu Hui‐Juan Li Wei‐Xia Duan Yu Duan Qin Yu Tian Zhang Ya‐Pei Sun Yuan‐Yuan Li Yong‐Sheng Liu Shang‐Cheng Xu |
| author_sort | Cong Liu |
| collection | DOAJ |
| description | Abstract Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity. |
| first_indexed | 2024-04-10T05:57:10Z |
| format | Article |
| id | doaj.art-4cc2785453f74591bb5a31f287df6924 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-10T05:57:10Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj.art-4cc2785453f74591bb5a31f287df69242023-03-03T08:59:14ZengWileyAdvanced Science2198-38442023-03-01107n/an/a10.1002/advs.202203869MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of CadmiumCong Liu0Hui‐Juan Li1Wei‐Xia Duan2Yu Duan3Qin Yu4Tian Zhang5Ya‐Pei Sun6Yuan‐Yuan Li7Yong‐Sheng Liu8Shang‐Cheng Xu9Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaInstitute of Rocket Force Medicine State Key Laboratory of Trauma Burns and Combined Injury Third Military Medical University Chongqing 400038 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning Chongqing 400060 P. R. ChinaAbstract Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.https://doi.org/10.1002/advs.202203869cadmiumhepatotoxicitymitochondrial calcium uniportermitophagyvoltage‐dependent anion‐selective channel protein 1 |
| spellingShingle | Cong Liu Hui‐Juan Li Wei‐Xia Duan Yu Duan Qin Yu Tian Zhang Ya‐Pei Sun Yuan‐Yuan Li Yong‐Sheng Liu Shang‐Cheng Xu MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium Advanced Science cadmium hepatotoxicity mitochondrial calcium uniporter mitophagy voltage‐dependent anion‐selective channel protein 1 |
| title | MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium |
| title_full | MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium |
| title_fullStr | MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium |
| title_full_unstemmed | MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium |
| title_short | MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium |
| title_sort | mcu upregulation overactivates mitophagy by promoting vdac1 dimerization and ubiquitination in the hepatotoxicity of cadmium |
| topic | cadmium hepatotoxicity mitochondrial calcium uniporter mitophagy voltage‐dependent anion‐selective channel protein 1 |
| url | https://doi.org/10.1002/advs.202203869 |
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