LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease

Area of Science:

• Mitochondrial biology
• Nephrology
• Molecular medicine

Background:

• Mitochondria are central to cellular metabolism, and their dysfunction is implicated in chronic kidney disease (CKD) pathogenesis.
• The role of Lon protease 1 (LONP1), a key mitochondrial protease, in CKD remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of LONP1 in the pathogenesis of CKD.
• To explore LONP1 as a potential therapeutic target for CKD treatment.

Main Methods:

• Assessed LONP1 expression in human and mouse CKD models.
• Utilized tubular-specific Lonp1 overexpression and deletion mouse models.
• Performed in vitro studies using renal tubular epithelial cells.
• Investigated the downstream effects of LONP1 downregulation on HMGCS2.
• Conducted computer-aided virtual screening to identify LONP1 activators.

Main Results:

• LONP1 expression was significantly decreased in patients and mice with CKD.
• Tubular-specific Lonp1 overexpression ameliorated renal injury and mitochondrial dysfunction in CKD models.
• Lonp1 deletion exacerbated renal injury and mitochondrial dysfunction.
• LONP1 downregulation led to mitochondrial accumulation of HMGCS2, impairing mitochondrial function.
• A novel LONP1 activator was identified and shown to attenuate renal fibrosis and mitochondrial dysfunction.

Conclusions:

• LONP1 plays a protective role in CKD pathogenesis.
• Targeting LONP1 activity represents a promising therapeutic strategy for managing CKD.