2. Academic Validation
  3. MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium

MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium

  • Adv Sci (Weinh). 2023 Jan 15;e2203869. doi: 10.1002/advs.202203869.
Cong Liu 1 2,  Hui-Juan Li 3,  Wei-Xia Duan 1 2,  Yu Duan 1 2,  Qin Yu 1 2,  Tian Zhang 1 4,  Ya-Pei Sun 1 5,  Yuan-Yuan Li 1 2,  Yong-Sheng Liu 1 2,  Shang-Cheng Xu 1 2
Affiliations

Affiliations

  • 1 Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, Chongqing, 400060, P. R. China.
  • 2 National Emergency Response Team for Sudden Poisoning, the First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, 400060, P. R. China.
  • 3 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400038, P. R. China.
  • 4 Bioengineering College of Chongqing University, Chongqing, 400044, P. R. China.
  • 5 School of Public Health, Nanjing Medical University, 211166, Nanjing, P. R. China.
PMID: 36642847 DOI: 10.1002/advs.202203869
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.

Keywords

cadmium; hepatotoxicity; mitochondrial calcium uniporter; mitophagy; voltage-dependent anion-selective channel protein 1.

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