Lo 2018 Am J Physiol Renal Physiol

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Lo S, MacMillan-Crow LA, Parajuli N (2018) Renal cold storage followed by transplantation impairs proteasome function and subsequently mitochondrial protein homeostasis. Am J Physiol Renal Physiol 316:F42-F53.

» PMID: 30303714

Lo S, MacMillan-Crow LA, Parajuli N (2018) Am J Physiol Renal Physiol

Abstract: Identification of renal cold storage (CS)-related pathways that lead to renal damage after transplantation (Tx) will help us design new pathway-specific therapies to improve graft outcome. Our recent report showed that mitochondrial function was compromised after CS alone, and this was exacerbated when CS was combined with Tx (CS/Tx). The goal of this study was to determine whether proteasome pathways are involved with exacerbation of mitochondrial dysfunction after CS/Tx. Kidneys of male rats and NRK cells were exposed to CS/Tx or rewarming (CS/RW), respectively. To compare CS-induced effects, kidney Tx without CS exposure (ATx) was also used. Our study provides the first evidence that chymotrypsin-like (ChT-L) peptidase activity of the proteasome declined only after CS/Tx or CS/RW, but not after CS or ATx. Interestingly, key mitochondrial respiratory proteins (SDHA and ATP5B) were detected in the detergent-insoluble fraction after CS/Tx or CS/RW. Pharmacologic inhibition of ChT-L activity in NRK cells also resulted in increased levels of SDHA and ATP5B in the insoluble fraction, as well as reduced activities of complexes I and II. On the other hand, antimycin A inhibition of mitochondrial respiration in NRK cells resulted in compromised ChT-L function and increased amounts of SDHA and ATP5B in the insoluble fraction. Our results suggest that mitochondrial respiratory dysfunction during CS precedes compromised ChT-L function after CS/Tx, and proteasome dysfunction further leads to altered mitochondrial protein homeostasis and reduced respiration in kidneys after CS/Tx. Therefore, therapeutics that could preserve mitochondrial and proteasome function during CS may provide beneficial outcomes following transplantation.

Keywords: Ubiquitin proteasome system, Cold storage, Mitochondria, Transplantation, NRK-52E Normal rat kidney proximal tubular cells Bioblast editor: Plangger M O2k-Network Lab: US AR Little Rock MacMillan-Crow LA

Labels: MiParea: Respiration, mt-Medicine 

Stress:Cryopreservation  Organism: Rat  Tissue;cell: Kidney, Other cell lines  Preparation: Permeabilized cells  Enzyme: Complex II;succinate dehydrogenase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS  Pathway: N, S, ROX  HRR: Oxygraph-2k