Abstract: TH-PO030
Cyclophilin D Interacts with PPARα to Regulate Fatty Acid Oxidation in Cisplatin AKI
Session Information
- AKI: Mechanisms - Primary Injury and Repair - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Jang, Hee-Seong, University of Nebraska Medical Center, Omaha, Nebraska, United States
- Noh, Mira, University of Nebraska Medical Center, Omaha, Nebraska, United States
- Padanilam, Babu J., University of Nebraska Medical Center, Omaha, Nebraska, United States
Background
Regardless of the etiology, acute kidney injury (AKI) involves aspects of mitochondrial dysfunction and ATP depletion. Fatty acid oxidation (FAO) is the preferred energy source of the kidney and is inhibited during AKI. A pivotal role for the mitochondrial matrix protein, cyclophilin D (CypD) in regulating overall cell metabolism is being unraveled. We hypothesize that mitochondrial interaction of proximal tubule CypD and PPARα modulate FAO in cisplatin-induced AKI (cisplatin AKI).
Methods
Using genetic and pharmacological intervention and protein-protein interaction studies, we investigated whether proximal tubule CypD modulates FAO in cisplatin AKI through mitochondrial CypD-PPARα binding and its sequestration.
Results
Cisplatin injury resulted in histological and functional damage in the kidney with downregulation of FAO genes and increase of intrarenal lipid accumulation. However, proximal tubule (PT)-specific deletion of CypD protected cisplatin-induced renal damage by inhibiting impairment of FAO and intrarenal lipid accumulation. Immunoprecipitation and BioID methods demonstrated mitochondrial translocation of PPARα and its binding to CypD and sequestration. This led to inhibition of nuclear translocation of PPARα and transcription of PPARα-regulated FAO genes during cisplatin AKI. Genetic or pharmacological inhibition of CypD suppressed mitochondrial CypD-PPARα binding in cisplatin AKI, preventing the impairment of FAO and intracellular lipid accumulation.
Conclusion
These results uncover a novel mechanism by which mitochondrial interaction between CypD and PPARα impairs FAO in cisplatin AKI. Targeting their interaction may be a potential therapeutic strategy to prevent energy depletion and cell death in AKI.
Funding
- NIDDK Support