Mitochondria-Derived Damage-Associated Molecular Patterns in Sepsis: From Bench to Bedside

Li, Sicheng; Hu, Qiongyuan; Huang, Jinjian; Wu, Xiuwen; Ren, Jianan

doi:10.1155/2019/6914849

Cited by 21 publications

(17 citation statements)

References 99 publications

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“…Mitochondrial structural and functional derangements in proximal tubular epithelial cells have also been reported in experimental sepsis models [ 5 ]. The inflammatory response in sepsis-induced kidney injury might be associated with the release of pro-apoptotic factors and mitochondria-derived DAMPs [ 25 ]. Moreover, the induction of apoptosis and functional alterations in podocytes and tubular cells after treatment with plasma from patients with sepsis-induced AKI suggests that circulating plasma factors augment kidney injury [ 26 ].…”

Section: Mitochondrial Dysfunction In Acute Kidney Injurymentioning

confidence: 99%

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

115

104

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Renal inflammation and tissue damage during acute kidney injury (AKI) and chronic kidney disease (CKD) have been linked to mitochondrial structural and functional alterations [1,2]. Mitochondria are a highly complex interconnected network of organelles that fulfill cellular energy needs. The kidney, an organ with high energy demands, is rich in mitochondria. Mitochondrial dysfunction arising from disturbances in the regulation of the mitochondrial electron transport chain (ETC), proton gradient, and membrane potential results in reduced adenosine triphosphate (ATP) and increased production of mitochondrial-derived reactive oxygen species (mROS), which promotes kidney injury and inflammation [3,4].

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Section: Mitochondrial Dysfunction In Acute Kidney Injurymentioning

confidence: 99%

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia¹,

Capili²,

Choi

2020

Kidney Res Clin Pract

115

104

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“…In addition, the gasdermin pore in the plasma membrane eventually executes pyroptosis, simultaneously causing the mitochondria to release its contents [ 32 ]. The ROS, mtDNA, and ATP released from injured mitochondria strongly promote pyroptosis by activating the inflammasome and the cleavage of caspase-1 [ 33 – 35 ]. Our results have shown that HGF protects the integrity of the mitochondrial plasma membrane, reduces the release of mitochondrial contents, leads to the scavenging of ROS or other mitochondrial damage-associated molecules and prevents pyroptosis [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

HGF alleviates septic endothelial injury by inhibiting pyroptosis via the mTOR signalling pathway

et al. 2020

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Background: Endothelial injury is one of the predominant pathophysiological characteristics of sepsis and is the major cause of sepsis-induced multiple organ failure. Endothelial pyroptosis is a fatal mechanism of endothelial injury in sepsis, and specific, effective therapies are lacking. Although hepatocyte growth factor (HGF) has been shown to have anti-apoptotic and anti-necrotic effects, whether it prevents pyroptosis to improve endothelial injury in sepsis remains unclear. Methods: Recombinant HGF was intravenously injected into mice with sepsis caused by caecal ligation puncture (CLP). Histopathological examination and transmission electron microscopy (TEM) were used to measure lung vascular endothelial injury. Lipopolysaccharide (LPS) was transfected into EA.hy926 cells to induce endothelial pyroptosis, and the cells were treated with HGF in the presence of inhibitors of c-Met and mTOR, namely, PHA-665752 and rapamycin, respectively. The mTOR signalling pathway and mitochondrial physiology were assessed using Western blot and flow cytometry. Results: Intravenous HGF effectively alleviated pulmonary vascular endothelial injury and acute lung injury in the septic mice. The TEM results of lung tissue revealed that HGF attenuated pulmonary vascular endothelial pyroptosis, which was confirmed in vitro. Transfected LPS induced the pyroptosis of EA.hy926 cells and damaged their paracellular permeability, and these effects were ameliorated by treating the cells with recombinant HGF. The protective effect of HGF against pyroptosis was dependent on c-Met/mTOR signalling. mTOR activation effectively protected mitochondrial physiology and decreased reactive oxygen species (ROS) production in EA.hy926 cells in vitro. Conclusions: These results demonstrated that HGF protected mitochondrial physiology by activating mTOR signalling to partially ameliorate endothelial pyroptosis and attenuate vascular endothelial injury and acute lung injury in sepsis animal model.

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“…The elevated ROS and RNS induces DNA strand break-mediated PARP activation causing reduction in the cellular NAD + level, oxidative phosphorylation abnormalities, and mPT induction [168]. All these processes lead to the release of various small molecules, such as ATP and succinate, and macromolecules, or their fragments, such as mitochondrial DNA, RNA, transcription factor, cytochrome C, cardiolipin and N-formyl peptides, collectively referred to as mitochondria-derived damage-associated molecular patterns (mtDAMPs) [169]. The mtDAMPs are recognised by their associated pattern recognition receptors that induce various inflammatory processes, overactivation of which is responsible for the development of sepsis and septic shock [170].…”

Section: Sepsis and Septic Shockmentioning

confidence: 99%

“…The mtDAMPs are recognised by their associated pattern recognition receptors that induce various inflammatory processes, overactivation of which is responsible for the development of sepsis and septic shock [170]. Due to mitochondrion's prokaryotic origin, mtDAMPs are similar to molecular patterns of most pathogens, and are likely to trigger excessive inflammatory reactions, which can aggravate sepsis to multi-organ dysfunction syndrome and death [169]. Activation of the inflammatory processes by mtDAMP can further damage mitochondria, forming a vicious circle that is a potential target regarding therapy.…”

Section: Sepsis and Septic Shockmentioning

confidence: 99%

Mitochondrial Protection by PARP Inhibition

Gallyas

Sümegi

2020

IJMS

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Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) polymerase (PARP) have recently been introduced in the therapy of cancers deficient in double-strand DNA break repair systems, and ongoing clinical trials aim to extend their use from other forms of cancer non-responsive to conventional treatments. Additionally, PARP inhibitors were suggested to be repurposed for oxidative stress-associated non-oncological diseases resulting in a devastating outcome, or requiring acute treatment. Their well-documented mitochondria- and cytoprotective effects form the basis of PARP inhibitors’ therapeutic use for non-oncological diseases, yet can limit their efficacy in the treatment of cancers. A better understanding of the processes involved in their protective effects may improve the PARP inhibitors’ therapeutic potential in the non-oncological indications. To this end, we endeavoured to summarise the basic features regarding mitochondrial structure and function, review the major PARP activation-induced cellular processes leading to mitochondrial damage, and discuss the role of PARP inhibition-mediated mitochondrial protection in several oxidative stress-associated diseases.

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Mitochondria-Derived Damage-Associated Molecular Patterns in Sepsis: From Bench to Bedside

Cited by 21 publications

References 99 publications

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

HGF alleviates septic endothelial injury by inhibiting pyroptosis via the mTOR signalling pathway

Mitochondrial Protection by PARP Inhibition

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