Abstract
BackgroundThe majority of transplanted kidneys are procured from deceased donors which all require exposure to cold storage (CS) for successful transplantation. Unfortunately, this CS leads to renal and mitochondrial damage but, specific mitochondrial targets affected by CS remain largely unknown. The goal of this study is to determine whether pathways involved with mitochondrial fusion or fission, are disrupted during renal CS.MethodsMale Lewis rat kidneys were exposed to cold storage (CS) alone or cold storage combined with transplantation (CS/Tx). To compare effects induced by CS, kidney transplantation without CS exposure (autotransplantation; ATx) was also used. Mitochondrial function was assessed using high resolution respirometry. Expression of mitochondrial fusion and fission proteins were monitored using Western blot analysis.ResultsCS alone (no Tx) reduced respiratory complex I and II activities along with reduced expression of the primary mitochondrial fission protein, dynamin related protein (DRP1), induced loss of the long form of Optic Atrophy Protein (OPA1), and altered the mitochondrial protease, OMA1, which regulates OPA1 processing. CS followed by Tx (CS/Tx) reduced complex I, II, and III activities, and induced a profound loss of the long and short forms of OPA1, mitofusin 1 (MFN1), and mitofusin 2 (MFN2) which all control mitochondrial fusion. In addition, expression of DRP1, along with its primary receptor protein, mitochondrial fission factor (MFF), were also reduced after CS/Tx. Interestingly, CS/Tx lead to aberrant higher molecular weight OMA1 aggregate expression.ConclusionsOur results suggest that CS appears to involve activation of the OMA1, which could be a key player in proteolysis of the fusion and fission protein machinery following transplantation. These findings raise the possibility that impaired mitochondrial fission and fusion may be unrecognized contributors to CS induced mitochondrial injury and compromised renal graft function after transplantation.
Highlights
Renal transplantation has been a clinical reality for almost 50 years, and improved success in recent years is attributed to the advent of tissue-typing protocols and superior immunosuppressive regimens
cold storage (CS) followed by Tx (CS/Tx) reduced complex I, II, and III activities, and induced a profound loss of the long and short forms of optic atrophy protein type 1 (OPA1), mitofusin 1 (MFN1), and mitofusin 2 (MFN2) which all control mitochondrial fusion
Our results suggest that CS appears to involve activation of the OMA1, which could be a key player in proteolysis of the fusion and fission protein machinery following transplantation
Summary
Renal transplantation has been a clinical reality for almost 50 years, and improved success in recent years is attributed to the advent of tissue-typing protocols and superior immunosuppressive regimens. The key variable is cold storage (CS); kidneys from living donors are generally excluded from CS, whereas those from deceased donors are subjected to cold preservation to allow transportation to recipient, and time for tissue typing and cross-matching procedures prior to transplantation. The mechanisms that mediate renal CS-induced mitochondrial damage remain elusive and are the focus of this study. The majority of transplanted kidneys are procured from deceased donors which all require exposure to cold storage (CS) for successful transplantation. This CS leads to renal and mitochondrial damage but, specific mitochondrial targets affected by CS remain largely unknown. The goal of this study is to determine whether pathways involved with mitochondrial fusion or fission, are disrupted during renal CS
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