Abstract: FR-PO163
Protease Inhibition Improves Renal Mitochondrial Function during Cold Storage and Transplantation
Session Information
- Mitochondriacs and More
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Transplantation
- 1701 Transplantation: Basic and Experimental
Authors
- MacMillan-Crow, Lee Ann, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Parajuli, Nirmala, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Tobacyk, Julia, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Shrum, Stephen A, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Background
Kidneys were the first successfully transplanted organs and are the most common organ transplant today. Cold storage (CS) of deceased donors is required for successful renal transplantation, but it also leads to renal and mitochondrial damage. During stressful conditions such as CS, mitochondrial fusion allows compensatory mixing of functional mitochondrial content with damaged mitochondria. Thus, impaired fusion can limit acute damage control and ultimately lead to loss of respiratory capacity and cell death. OPA1 is a key mitochondrial fusion protein and is regulated by the mitochondrial protease OMA1. The goal of this study was to evaluate how CS alters mitochondrial fusion machinery and to evaluate the therapeutic benefit of OMA1 inhibition.
Methods
Male rodent (Lewis) kidneys were isolated and cold stored for 0 or 18 hr and then transplanted (CS/Tx) in a naïve Lewis rat followed by right nephrectomy. Mitochondrial function was assessed via high resolution respirometry and ATP measurement. Mitochondrial fusion and fission pathways were monitored using western blot. A novel method was developed to measure OMA1 activity. Renal injury was assessed by serum creatinine and PAS staining.
Results
Data clearly revealed that CS worsens mitochondrial function when compared to transplantation without CS. Combined CS/Tx lead to OPA1 inhibition and increased OMA1 activity along with an altered protein expression of OMA1. Inhibition of OMA1 using phenanthroline during CS lead to increased OPA1 expression and improved mitochondrial function. Further studies will characterize the benefit of mitochondrial targeted phenanthroline as a novel therapy to improve mitochondrial and renal function during CS/Tx.
Conclusion
Our results suggest that CS/Tx alters the mitochondrial protease, OMA1, and that OMA1 inhibition improves mitochondrial function. These findings raise the possibility that impaired mitochondrial dynamics may be an unrecognized contributor to cold storage induced injury and compromised renal graft function after transplantation.
Supported in part by and AHA 16SDG276000026 (NP) and AHA 16PRE30830010 (SS); as well as NIH T32GM106999 (SS), T32GM106999 (JT).
Funding
- Other NIH Support