Increased Succinate Accumulation Induces ROS Generation in In Vivo Ischemia/Reperfusion-Affected Rat Kidney Mitochondria.

Justina Kamarauskaite,Arvydas Strazdauskas,Rasa Baniene,Darius Trumbeckas,Sonata Trumbeckaite,Erika Di Zazzo

doi:10.1155/2020/8855585

Justina Kamarauskaite, Arvydas Strazdauskas + Show 4 more

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https://doi.org/10.1155/2020/8855585

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Abstract

Mitochondria are recognized as main reactive oxygen species (ROS) producers, involving ROS generation by mitochondrial complexes I and III. Lately, the focus has been shifting to the ROS generation by complex II. Contribution of complex II (SDH) to ROS generation still remains debatable, especially in in vivo settings. Moreover, it is not completely defined at what time of ischemia the first alterations in mitochondria and the cell begin, which is especially important with renal arterial clamping in vivo during kidney surgery, as it predicts the postischemic kidney function. The aim of this study on an in vivo rat kidney ischemia/reperfusion model was to determine if there is a connection among (a) duration of kidney ischemia and mitochondrial dysfunction and (b) succinate dehydrogenase activity, succinate accumulation, and ROS generation in mitochondria at low and saturating succinate concentrations. Our results point out that (1) mitochondrial disturbances can occur even after 30 min of kidney ischemia/reperfusion in vivo and increase progressively with the prolonged time of ischemia; (2) accumulation of succinate in cytosol after ischemia/reperfusion correlated with increased H2O2 generation mediated by complex II, which was most noticeable with physiological succinate concentrations; and (3) ischemia/reperfusion induced cell necrosis, indicated by the changes in LDH activity. In conclusion, our new findings on the accumulation of succinate in cytosol and changes in SDH activity during kidney ischemia/reperfusion may be important for energy production after reperfusion, when complex I activity is suppressed. On the other hand, an increased activity of succinate dehydrogenase is associated with the increased ROS generation, especially with physiological succinate concentrations. All these observations play an important role in understanding the mechanisms which occur in the early phase of ischemia/reperfusion injury in vivo and may provide new ideas for novel therapeutic approaches or injury prevention; therefore, more detailed studies are necessary in the future.

Highlights

Ischemia/reperfusion (I/R) injury of the kidney is a complex process; it involves free radical overproduction, inflammation, disturbances in microcirculation, and damage of mitochondria, leading to postischemic kidney dysfunction [1]
SDH, as was shown in our study, is involved in reactive oxygen species (ROS) production, especially at physiological succinate concentrations (Figure 3(c)), and this is in line with Quinlan et al.’s observation that ROS production at complex II in muscle mitochondria occurs at low concentration of succinate when the succinate-binding site is not occupied by substrate and that ROS generation is inhibited by excess of succinate [8]
Our results point out that (1) mitochondrial disturbances can occur even after 30 min of kidney ischemia/reperfusion in vivo and increase progressively with the prolonged time of ischemia; (2) accumulation of succinate in cytosol after ischemia/reperfusion correlated with increased H2O2 generation mediated by complex II, which was most noticeable with physiological succinate concentrations; and (3) ischemia/reperfusion induced cell necrosis, indicated by the changes in Lactate dehydrogenase (LDH) activity

Summary

Introduction

Ischemia/reperfusion (I/R) injury of the kidney is a complex process; it involves free radical overproduction, inflammation, disturbances in microcirculation, and damage of mitochondria, leading to postischemic kidney dysfunction [1]. It has already been shown that I/R leads to the reduced activity of mitochondrial respiratory chain complexes, ATP depletion, calcium accumulation, mitochondrial permeability transition pore opening, and an increase in reactive oxygen species (ROS) production; the BioMed Research International complete mechanisms and the interaction between these processes are not fully elucidated. It is not clear at what time of ischemia the first alterations in mitochondria and the cell begin, what duration of ischemia is already critical for the mitochondria, and how mitochondrial impairment progresses during ischemia. This is extremely important during renal surgery, when arteria is clamped for a certain period, as it determines the postischemic kidney recovery processes

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