Abstract: FR-PO178

Gender Differences in Renal Mitochondrial Injury during Sepsis

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • MacMillan-Crow, Lee Ann, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
  • Mayeux, Philip R., University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Background

Acute kidney injury (AKI) is a frequently encountered complication of sepsis. Sepsis accounts for about 50% of AKI cases in intensive care units and patients with sepsis complicated by AKI have markedly worse prognosis and have a higher mortality rate. Numerous studies, including our own, have reported the involvement of mitochondrial damage and oxidant production during sepsis. The goal of this study was to evaluate whether gender differences exist in the extent of mitochondrial damage using a murine model of sepsis.

Methods

Cecal ligation and puncture (CLP) was performed in male and female CD1 mice to induce sepsis. Briefly, the cecum was punctured twice with a 21-gauge needle, followed by a right nephrectomy. Animals received antibiotics and fluid resuscitation at 6 h and every 12 h thereafter. Mitochondrial function was assessed via high resolution respirometry (HRR) and ATP measurement. Mitochondrial fusion and fission pathways were monitored using western blot.

Results

Male mice exposed to CLP (18 hr) showed a significant decline in complex I, II, and III activities compared to sham animals. However, only complex I was inactivated in female mice exposed to CLP (18 hr). Interestingly, baseline (sham) complex II and IV activities were significantly higher in female mice, compared to male mice. In addition, studies show that sepsis in our male model leads to loss of the long form of Optic Atrophy Protein (OPA1), which normally fuses the inner mitochondrial membrane between mitochondria, as an essential part of the overall fusion process. OPA1 is cleaved to the short form by two zinc metalloproteinases, OMA1 and YME1L. OMA1 is considered a stress-induced protease and appears to be activated in our male sepsis model, but not in female mice. Interestingly, sepsis in female mice induced protein expression of the mitofusions (MFN1/2) proteins which regulate outer mitochondrial membrane fusion, which was not observed in male mice. Survival studies showed that female mice exposed to CLP were more likely to die compared to male mice.

Conclusion

Our results suggest that sepsis induces gender dependent differences in mitochondrial damage and remodeling via fusion/fission processes. These findings raise the possibility that altered mitochondrial dynamics may be an unrecognized contributor to gender specific responses to sepsis induced AKI.

Funding

  • Other NIH Support