Kidney Week

Abstract: SA-PO0871

Inhibition of Mitochondrial Pyruvate Carrier Protects Aging Kidneys

Session Information

• Top Trainee Posters - 3
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 01:42 PM - 01:48 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1500 Health Maintenance, Nutrition, and Metabolism

Authors

• Hurtado, Kevin A., Washington University in St Louis, St. Louis, Missouri, United States

Kevin A. Hurtado, PhD

• Patel, Maulik, Washington University in St Louis, St. Louis, Missouri, United States

Maulik Patel, MSc, PhD

• Laha, Dipranjan, Washington University in St Louis, St. Louis, Missouri, United States

Dipranjan Laha

• Hammoud, Safaa, Washington University in St Louis, St. Louis, Missouri, United States

Safaa Hammoud, PhD

• Jain, Sanjay, Washington University in St Louis, St. Louis, Missouri, United States

Sanjay Jain, MD, PhD

• Finck, Brian, Washington University in St Louis, St. Louis, Missouri, United States

Brian Finck

• Gewin, Leslie S., Washington University in St Louis, St. Louis, Missouri, United States

Leslie S. Gewin, MD, FASN

Background

Kidney cortical tubules rely on fatty acid oxidation (FAO) to support high metabolic demands. During renal aging, FAO declines and glucose metabolism increases, but the functional significance of this metabolic change is unclear. Glucose-derived pyruvate enters the mitochondria via the mitochondrial pyruvate carrier (MPC) for oxidation in the tricarboxylic acid (TCA) cycle. MPC inhibitors are under clinical investigation to treat diabetes, but the role of MPC inhibition in the aging kidney remains unexplored. We hypothesize that inhibition of MPC improves age-related kidney injury.

Methods

Single nuclear RNA sequencing (snRNA-seq) was performed on aged human kidneys (>60 years compared to <40 years) and kidneys from aged mice (22 months) +/- MSDC-0160, an MPC inhibitor used in clinical trials, from the NIH-sponsored Interventions Testing Program (ITP). We measured fibrosis by picrosirius red staining and Collagen I immunoblotting. Mitochondrial function was measured on MSDC-0160-treated kidney tissue using high-resolution respirometry (Oroboros). We generated mice lacking MPC2, required for MPC function, in kidney tubules using Pax8-rTTA;tetO-Cre (Mpc2^CKO). To study MPC inhibition's effect on mitophagy, we treated Mito-QC reporter mice with MSDC-0160. We measured AMP:ATP and performed stable isotope tracer studies with ¹³C-palmitate on freshly isolated tubules from Mpc2^CKO and floxed mice using mass spectrometry. We measured activation of AMP-activated protein kinase (AMPK) by immunoblotting.

Results

snRNA-seq data revealed increased MPC gene expression in the murine and human aged kidneys compared to young controls. Aged mice had reduced expression of FAO-related genes, which was partially restored with MSDC-0160 treatment. Aged mice showed increased Sirius Red+ staining and collagen I protein expression, an effect significantly reduced by MSD-0160 treatment. MSDC-0160-treated kidney tissue had increased mitochondrial respiration by Oroboros, and mitophagywas increased in Mito-QC mice treated with MSDC-0160. Stable isotope studies revealed increased ¹³C-labeled TCA metabolites in Mpc2^CKO tubules ex vivo, showing increased FAO. AMP:ATP was elevated in Mpc2^CKO tubules, suggesting increased AMPK activity, which was confirmed by immunoblots.

Conclusion

These data suggest that blocking MPC decreased aged associated-fibrosis, restored FAO, and enhanced mitophagy in the aging kidney, likely through increased AMPK activity.