LONP1 Targets HMGCS2 to Protect Mitochondrial Function and Attenuate Chronic Kidney Disease

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2023 Jan 11

PMID 36629048

Authors

Mi Bai

Mengqiu Wu

Mingzhu Jiang

Jia He

Xu Deng

Shuang Xu

Jiaojiao Fan

Mengqiu Miao

Ting Wang

Yuting Li

Xiaowen Yu

Lin Wang

Yue Zhang

Songming Huang

Li Yang

Zhanjun Jia

Aihua Zhang

Affiliations

Soon will be listed here.

Abstract

Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular-specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer-aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD.

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