Kidney Week

Abstract: FR-PO1198

Reduced Cardiolipin Drives Defects in ATP Production and May Contribute to Reduced GFR and CKD Progression

Session Information

• CKD: Mechanisms, AKI, and Beyond - 2
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Opurum, Precious Chinonyerem, Diabetes and Metabolic Research Center, University of Utah, Salt Lake City, Utah, United States

Precious Chinonyerem Opurum, PhD

• Decker, Stephen, Diabetes and Metabolic Research Center, University of Utah, Salt Lake City, Utah, United States

Stephen Decker, PhD

• Stuart, Deborah, University of Utah Health, Salt Lake City, Utah, United States

Deborah Stuart

• Nicholson, Rebekah, Diabetes and Metabolic Research Center, University of Utah, Salt Lake City, Utah, United States

Rebekah Nicholson, MS, RD

• Summers, Scott, Diabetes and Metabolic Research Center, University of Utah, Salt Lake City, Utah, United States

Scott Summers, PhD

• Sanchez, Alejandro, University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, United States

Alejandro Sanchez, MD

• Ramkumar, Nirupama, University of Utah Health, Salt Lake City, Utah, United States

Nirupama Ramkumar, MD, MPH, FASN

• Funai, Katsuhiko, Diabetes and Metabolic Research Center, University of Utah, Salt Lake City, Utah, United States

Katsuhiko Funai, PhD

Background

Chronic kidney disease (CKD) affects 15% of U.S. adults, with most individuals unaware of their illness. Mitochondrial dysfunction—particularly impaired oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane (IMM)−is a hallmark of CKD. Cardiolipin (CL), a phospholipid primarily located in the IMM, is essential for maintaining mitochondrial bioenergetics. Although reduced CL has been associated with mitochondrial dysfunction in various organs, its role in the kidney remains unclear. This study aims to evaluate whether CL depletion contributes to renal mitochondrial dysfunction and CKD progression.

Methods

We assessed CL levels across four mouse models of AKI/CKD: ischemia-reperfusion injury (IRI), unilateral ureteral obstruction (UUO), high-fat diet (HFD), and high-fat/high-salt (HFHS). To investigate causality, we developed proximal tubule-specific cardiolipin synthase knockout mice (CLS-PTKO) using SGLT2-Cre recombinase. Renal function was assessed through glomerular filtration rate (GFR), blood, urine, and histological analysis. Mitochondrial respiration, fatty acid oxidation (FAO), and ATP production were assessed using high-resolution respirometry and fluorimetry to confirm bioenergetic defects associated with loss of CL.

Results

Our data shows a consistent reduction in CL across all four models. Preliminary data from CLS-PTKO model shows reduced GFR (283.93 ± 45.09 μL/min), robust reduction in ATP production (2969.49 ± 516.45 pmol*sec^-1*mg_protein^-1) and higher FAO trend (269.56 ± 2.48 pmol*sec^-1*mg_protein^-1) compared to that of the floxed controls: GFR (225.83 ± 10.11 μL/min), ATP (5695.90 ± 270.22 pmol*sec^-1*mg_protein^-1, p=0.0018) and FAO (220.50 ± 56.56 pmol*sec^-1*mg_protein^-1) without changes in respiration, suggesting impaired bioenergetic efficiency and potential compensatory mechanism for energy production.

Conclusion

These data reveal early bioenergetic defects due to CL loss, which may contribute to CKD progression. Future studies using the HFHS model aim to accelerate the burden of CLS deletion in older mice. This research highlights the critical role of CL in proximal tubule mitochondrial function and renal health.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20258hyjp3sn