LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity

Shun Zhang; Subo Qian; Hailong Liu; Ding Xu; Weimin Xia; Huangqi Duan; Chen Wang; Shenggen Yu; Yingying Chen; Ping Ji; Shujun Wang; Xingang Cui; Ying Wang; Haibo Shen

Redox Biology (Oct 2023)

LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity

Shun Zhang,
Subo Qian,
Hailong Liu,
Ding Xu,
Weimin Xia,
Huangqi Duan,
Chen Wang,
Shenggen Yu,
Yingying Chen,
Ping Ji,
Shujun Wang,
Xingang Cui,
Ying Wang,
Haibo Shen

Affiliations

Shun Zhang: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Subo Qian: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding author. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Yangpu, Shanghai 200092, China.
Hailong Liu: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Ding Xu: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Weimin Xia: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Huangqi Duan: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Chen Wang: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Shenggen Yu: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Yingying Chen: Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Ping Ji: Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Shujun Wang: Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xingang Cui: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding authors. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Yangpu, Shanghai 200092, China.
Ying Wang: Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Corresponding author. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Haibo Shen: Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding authors. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Yangpu, Shanghai 200092, China.

Journal volume & issue: Vol. 66
p. 102860

Abstract

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Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2−/− mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2Ser27 and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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