Mitochondria-meditated pathways of organ failure upon inflammation

Abstract

Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…Over the past decades, mitochondria have been well recognized as major regulators that control heart function and cardiomyocyte viability under physiological and pathological conditions. 4,5 Structurally, mitochondrial homeostasis is closely regulated by mitochondrial dynamics, including mitochondrial fission, mitochondrial fusion, and mitophagy. 6,7 Ample evidence has indicated that I/R injury primarily involves multiple factors that converge on provoking the onset of mitochondrial fission.…”

“…7 In the failing heart, the overexpression of OPA1 reverses mitochondrial function and improves cardiac performance. 31 Mechanistically, OPA1 expression is potentially regulated by the AMPK pathway, 5 which is also reported to be associated with mitophagy modification. Along with the well-documented role played by OPA1-related mitochondrial fusion and mitophagy in cardioprotection, it is very worthwhile to explore whether melatonin protects the reperfused heart by activating OPA1-related mitochondrial fusion and mitophagy in a manner dependent on the AMPK signaling pathway.…”

Signalling pathways involved in p47phox‐dependent reactive oxygen species in platelets of endotoxemic rats

“…Studies have shown that LPS increases NADPH oxidase expression and activation in different tissues and that the boost of ROS production by LPS is largely dependent on NADPH oxidase activity . ROS modulates a variety of physiopathological effects, such as the production of pro‐inflammatory cytokines, which is a hallmark of endotoxaemia and multiorgan dysfunction . c‐Src and PI3K are important enzymes involved in the modulation of NADPH oxidase activity mainly through p47 phox phosphorylation .…”

“…Thrombocytopenia is also a hallmark of endotoxemia, and has been associated with a worse clinical outcome as evidenced by elevated risk of bleeding, many times resulting in death . Overproduction of reactive oxygen species (ROS) by LPS is detrimental to the normal functioning of organs, thus contributing to multiorgan failure …”

Effect of magnesium on reducing the UV‐induced oxidative damage in marrow mesenchymal stem cells

“…Mitochondria are important organelle in cells, which perform many roles beyond energy production, including the generation of ROS, redox molecules and metabolites, regulation of cell signaling and cell death, and biosynthetic metabolism. 21,22 Therefore, it is not surprising mitochondria dysfunction is an important inducing factor of many diseases. 23 Oxidative stress plays a critical role in the mitochondria dysfunction.…”