Mitochondrial mechanisms and therapeutics in ischaemia reperfusion injury

Abstract

Acute kidney injury (AKI) remains a major problem in critically unwell children and young adults. Ischaemia reperfusion (IR) injury is a major contributor to the development of AKI in a significant proportion of these cases and mitochondria are increasingly recognised as being central to this process through generation of a burst of reactive oxygen species early in reperfusion. Mitochondria have additionally been shown to have key roles in downstream processes including activation of the immune response, immunomodulation, and apoptosis and necrosis. The recognition of the central role of mitochondria in IR injury and an increased understanding of the pathophysiology that undermines these processes has resulted in identification of novel therapeutic targets and potential biomarkers. This review summarises a variety of therapeutic approaches that are currently under exploration and may have potential in ameliorating AKI in children in the future.

Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair

“…The intracellular Ca 2+ level further increases, which activates the calpains causing injury to the cell structure and cell death [8]. Restoration of normoxemia leads to the production of large amounts of ROS, together with a reduction in the antioxidant capacity [20]. This burst of ROS production was thought to be due to a generalised dysregulation of the electron transport chain with electrons leaking out at non-specific sites [21].…”

“…This massive amount of mitochondrially produced ROS is responsible for the activation of various injurious pathways through carbonylation of proteins or lipid peroxidation. This may contribute to injury of the cell membranes, the cytoskeleton and DNA and may lead to a disruption of ATP generation and induction of mPTP [20]. Additionally, the combination of ROS, dysfunctioning of the mitochondrial machinery and increase in mitochondrial Ca 2+ load causes opening of the mPTP and release of substances like cytochrome C, succinate and mitochondrial DNA (mtDNA), which are able to induce cell death through apoptosis and necrosis and may act as danger/damage associated molecular patterns (DAMPs) entailing activation of the innate and subsequently the adaptive immune system [23][24][25][26].…”

“…Recent insights in the pathophysiological mitochondrial mechanisms and general understanding of the pivotal role of the mitochondria in IRI has led to various strategies targeting mitochondria with the aim to reduce IRI including limiting oxidative stress and mitochondrial ROS generation [20]. Both lipophilic cations and mitochondrial targeted proteins have been developed to deliver antioxidants to the mitochondria [27].…”

Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

“…We performed Gene Ontology (GO) enrichment analysis to determine the significant biological pathways associated with target genes modified by iPSC-EV treatment. As shown in Figure 6a, the group of genes modulated by iPSC-EV were mainly associated with molecular functions such as glutathione redox reactions, Nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response, superoxide radical degradation, mitochondrial dysfunction, sirtuins pathways, and endothelin-1 signalling (Figure 6a), which are likely involved in the renal metabolic response during IRI [23].…”

Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models

“…1,4,5 Thus, much attention has been paid to mitochondria in efforts to understand the pathogenesis of kidney diseases and thereby identify therapeutic targets. [6][7][8] In animal studies, several methods are used to evaluate the intrinsic mitochondrial status of the kidney; however, these have some limitations in quantitative capability and precision. One direct method is to measure the oxygen consumption rate of isolated mitochondria.…”