Abstract
BackgroundHypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear.MethodsWe evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7–37 °C.ResultsLowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold.ConclusionsLowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation.
Highlights
Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation
Lowering temperature dramatically decreases mitochondrial oxygen consumption, in accord of a Q 10 effect To assess the influence of temperature, whole kidney oxygen consumption was measured in a closed kidney perfusion model at different temperatures, both in an increasing and decreasing curve (Fig. 1a)
Lowering of temperature from 37 °C to just below room temperature, 17 °C, provoked a strong decrease in oxygen consumption, with oxygen consumption stabilizing at temperatures below 17 °C
Summary
Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. The exact effect of hypothermic kidney preservation on mitochondrial function remains unclear. To expand the donor pool, an increasing number of suboptimal organs are accepted [1, 2]. These suboptimal, or socalled extended criteria donor organs, are more susceptible to the ischemic periods during procurement, preservation, and eventually transplantation [3]. Several techniques are employed to mitigate organ damage, such as the inclusion of antioxidants in preservation solutions and the use of oxygenated hypothermic machine perfusion (HMP), which both reduce the formation of ROS and improve post-transplantation graft function [5,6,7,8]. The beneficial effects of forced cooling are attributed to the deceleration of all metabolic processes, resulting in a hypometabolic state with decreased mitochondrial activity as reflected by lower oxygen consumption [9]
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