Kidney Week

Abstract: TH-PO023

Effects of Tubular Mitochondrial Pyruvate Carrier 1 Deletion on Redox Metabolism

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

• Steinbach, Emily J., University of Iowa, Iowa City, Iowa, United States

Emily J. Steinbach,

• Rauckhorst, Adam J., University of Iowa, Iowa City, Iowa, United States

Adam J. Rauckhorst,

• Wen, Hsiang M., University of Iowa, Iowa City, Iowa, United States

Hsiang M. Wen,

• Mapuskar, Kranti A., University of Iowa, Iowa City, Iowa, United States

Kranti A. Mapuskar,

• Allen, Bryan, University of Iowa, Iowa City, Iowa, United States

Bryan Allen,

• Spitz, Douglas R., University of Iowa, Iowa City, Iowa, United States

Douglas R. Spitz,

• Coleman, Mitchell C., University of Iowa, Iowa City, Iowa, United States

Mitchell C. Coleman,

• Taylor, Eric, University of Iowa, Iowa City, Iowa, United States

Eric Taylor,

• Zepeda-Orozco, Diana, University of Iowa, Iowa City, Iowa, United States

Diana Zepeda-Orozco,

Background

Kidney injury results in mitochondrial dysfunction, oxidative stress, change to tubular glycolytic metabolism, and disruption of lactate and pyruvate metabolism. Pyruvate treatment is protective in different kidney injury models. The Mitochondrial Pyruvate Carrier 1 (MPC1) transports pyruvate from the cytosol into the mitochondrial matrix and mediates the metabolic decision committing glycolytic carbon to mitochondrial oxidative phosphorylation. Understanding the implication of impaired tubular mitochondrial pyruvate transport may provide critical knowledge on the effect of mitochondrial metabolic adaptations in redox balance and injury response.

Methods

Pax8^Cre was bred into the Mpc1^f/f mouse line to generate Pax8^Cre+/-Mpc1^f/f (Tu-MPC1-KO) and Pax8^Cre-/-Mpc1^f/f (Tu-MPC1-WT) littermates to disrupt MPC1 in tubular epithelial cells. Mice 8-13 weeks of age were assessed for renal function and biomarkers of kidney injury. C¹³-lactate/C¹³-pyruvate tracing was employed to determine the metabolic consequences of TMPC1-KO. Finally, upon sacrifice markers of oxidative stress were studied and kidney tissue was examined histologically. A second cohort of Tu-MPC1-KO and –WT mice underwent cisplatin-induced kidney injury to evaluate survival.

Results

Tu-MPC1-KO resulted in accumulation of C¹³ labeled lactate/pyruvate and the concomitant decrease of C¹³ labeled TCA cycle intermediate metabolites. Significant reduction of C¹³ incorporation into glutamine suggests that mitochondrial oxidative metabolism may be sustained via glutaminolysis. Tu-MPC1-KO mice show no difference in renal histology or renal function compared to TMPC1-WT. Tu-MPC1-KO kidney tissue had a significant increase in oxidative stress markers including 3-nitrotyrosine, % total glutathione as glutathione disulfide, and MnSOD activity. Finally, while Tu-MPC1-KO mice exhibited increased markers of oxidative stress prior to cisplatin treatment compared to WT, no significant difference in survival was observed.

Conclusion

In vivo inhibition of tubular mitochondrial pyruvate transport leads to disruption of renal redox metabolism and increased oxidative stress markers in renal tubule cells, which does not affect survival after cisplatin-induced CKD.

Funding

• Other NIH Support