2. Academic Validation
  3. Alcohol dehydrogenase 1 is a tubular mitophagy-dependent apoptosis inhibitor against septic acute kidney injury

Alcohol dehydrogenase 1 is a tubular mitophagy-dependent apoptosis inhibitor against septic acute kidney injury

  • Exp Cell Res. 2023 Oct 6:113804. doi: 10.1016/j.yexcr.2023.113804.
Yang Zheng 1,  Juan-Juan Cai 2,  Xue Yang 3,  Zi-Qiang Shao 4,  Jing-Quan Liu 4,  Xiang-Hong Yang 4,  Ren-Hua Sun 4,  Bang-Chuan Hu 4,  Shi-Jing Mo 5,  Lan-Juan Li 6
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China; Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
  • 2 Department of Pathology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
  • 3 Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
  • 4 Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China.
  • 5 Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China; Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China. Electronic address: moshijing@hmc.edu.cn.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China. Electronic address: ljli@zju.edu.cn.
PMID: 37806378 DOI: 10.1016/j.yexcr.2023.113804
Abstract

Alcohol dehydrogenase 1 (ADH1) is an alcohol-oxidizing Enzyme with poorlydefined biology. Here we report that ADH1 is highly expressed in kidneys of mice with lethal endotoxemia and is transcriptionally upregulated in tubular cells by lipopolysaccharide (LPS) stimuli through TLR4/NF-κB cascade. The Adh1 knockout (Adh1KO) mice with lethal endotoxemia displayed increased susceptibility to acute kidney injury (AKI) but not systemic inflammatory response. Adh1KO mice develop more severe tubular cell Apoptosis in comparison to Adh1 wild-type (Adh1WT) mice during course of lethal endotoxemia. ADH1 deficiency facilitates the LPS-induced tubular cell Apoptosis in a caspase-dependent manner. Mechanistically, ADH1 deficiency dampens tubular Mitophagy that relies on PINK1-Parkin pathway characterized by the reduced membrane potential, Reactive Oxygen Species (ROS) and release of fragmented mtDNA to cytosol. Kidney-specific overexpression of PINK1 and Parkin by adeno-associated viral vector 9 (AAV9) delivery ameliorates AKI exacerbation in Adh1KO mice with lethal endotoxemia. Our study supports the notion that ADH1 is critical for blockade of tubular Apoptosis mediated by Mitophagy, allowing the rapid identification and targeting of alcohol-metabolic route applicable to septic AKI.

Keywords

Acute kidney injury; Alcohol dehydrogenase 1; Mitophagy; Sepsis.

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