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

doi:10.1016/j.redox.2023.102860

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

Redox Biol. 2023 Oct:66:102860. doi: 10.1016/j.redox.2023.102860. Epub 2023 Aug 22.

Authors

Shun Zhang¹, Subo Qian², Hailong Liu¹, Ding Xu¹, Weimin Xia¹, Huangqi Duan¹, Chen Wang¹, Shenggen Yu¹, Yingying Chen³, Ping Ji³, Shujun Wang³, Xingang Cui⁴, Ying Wang⁵, Haibo Shen⁶

Affiliations

¹ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
² Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address: qiansubo@xinhuamed.com.cn.
³ 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.
⁴ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address: cuixingang@163.com.
⁵ 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. Electronic address: ywang@sibs.ac.cn.
⁶ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address: shenhaibo@xinhuamed.com.cn.

Abstract

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 MFN2^Ser27 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.

Keywords: Acute kidney injury (AKI); Chronic kidney disease (CKD); Leucine-rich repeat kinase 2 (LRRK2); Mitochondrial damages; Mitofusin 2 (MFN2); Proximal tubular cell (PTC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / genetics
Animals
GTP Phosphohydrolases / genetics
Humans
Kidney
Kidney Tubules, Proximal
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Mice
Mitochondria / genetics
Mitochondrial Proteins / genetics
Renal Insufficiency, Chronic*

Substances

MFN2 protein, human
GTP Phosphohydrolases
Mitochondrial Proteins
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2