Mitochondrial quality control mechanisms as potential therapeutic targets in sepsis-induced multiple organ failure

Wu, You; Yao, Yong‐Ming; Lu, Zhongqiu

doi:10.1007/s00109-019-01756-2

Cited by 60 publications

(60 citation statements)

References 121 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After the cell separates the damaged mitochondrial region through mitochondrial fission, there are two sets of daughter mitochondria that either have increased membrane potential (presumably high‐quality mitochondria) or have decreased membrane potential (presumably low‐quality mitochondria). Timely and effective clearance of low‐quality mitochondria via mitophagy contributes to the preservation of high‐quality mitochondria . In compression‐exposed human NP cells, mitochondrial fission is activated and mitophagic flux is blocked, which leads to the accumulation of damaged mitochondria, resulting in mitochondrial homeostatic imbalance and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Timely and effective clearance of low-quality mitochondria via mitophagy contributes to the preservation of high-quality mitochondria. 4,[65][66][67][68] In compression-exposed human NP cells, mitochondrial fission is activated and mitophagic flux is blocked, which leads to the accumulation of damaged mitochondria, resulting in mitochondrial homeostatic imbalance and apoptosis. We used MitoQ to maintain the balance of mitochondrial dynamics and relieve the blockage of mitophagic flux, which reversed mitochondrial dysfunction and NP cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

View full text Add to dashboard Cite

Objective Mitochondrial dysfunction, oxidative stress and nucleus pulposus (NP) cell apoptosis are important contributors to the development and pathogenesis of intervertebral disc degeneration (IDD). Here, we comprehensively evaluated the effects of mitochondrial dynamics, mitophagic flux and Nrf2 signalling on the mitochondrial quality control, ROS production and NP cell survival in in vitro and ex vivo compression models of IDD and explored the effects of the mitochondria‐targeted anti‐oxidant MitoQ and its mechanism. Material and methods Human NP cells were exposed to mechanical compression to mimic pathological conditions. Results Compression promoted oxidative stress, mitochondrial dysfunction and NP cell apoptosis. Mechanistically, compression disrupted the mitochondrial fission/fusion balance, inducing fatal fission. Concomitantly, PINK1/Parkin‐mediated mitophagy was activated, whereas mitophagic flux was blocked. Nrf2 anti‐oxidant pathway was insufficiently activated. These caused the damaged mitochondria accumulation and persistent oxidative damage. Moreover, MitoQ restored the mitochondrial dynamics balance, alleviated the impairment of mitophagosome‐lysosome fusion and lysosomal function and enhanced the Nrf2 activity. Consequently, damaged mitochondria were eliminated, redox balance was improved, and cell survival increased. Additionally, MitoQ alleviated IDD in an ex vivo rat compression model. Conclusions These findings suggest that comodulation of mitochondrial dynamics, mitophagic flux and Nrf2 signalling alleviates sustained mitochondrial dysfunction and oxidative stress and represents a promising therapeutic strategy for IDD; furthermore, our results provide evidence that MitoQ might serve as an effective therapeutic agent for this disorder.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Autophagy can non-selectively or selectively eliminate damaged proteins and organelles by forming a double-membrane autophagosome, which fuses with lysosomes (Wu et al, 2019). Mitophagy is the selective autophagy of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Beclin-1 interacts with the class III phosphatidylinositol 3-kinase (PtdIns3K) to initiate autophagy and participates in later steps involving the fusion of autophagosomes to lysosomes (Zhong et al, 2009). LC3 binds to autophagosome membranes to form a complete autophagosome that fuses with lysosomes for degradation (Wu et al, 2019). P62 interacts with LC3 II to target aggregates for autophagy-specific degradation (Parzych and Klionsky, 2014).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Zhao

Feng

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Acute kidney injury (AKI) is often secondary to sepsis. Previous studies suggest that damaged mitochondria and the inhibition of autophagy results in AKI during sepsis, but dexmedetomidine (DEX) alleviates lipopolysaccharide (LPS)-induced AKI. However, it is uncertain whether the renoprotection of DEX is related to autophagy or the clearance of damaged mitochondria in sepsis-induced AKI. Methods: In this study, AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). The rats were also pretreated with DEX (30 mg/kg, i.p.) 30 min before the injection of LPS. The structure and function of kidneys harvested from the rats were evaluated, and the protein levels of autophagy-related proteins, oxidative stress levels, and apoptosis levels were measured. Further, atipamezole (Atip) and 3-Methyladenine (3-MA), which are inhibitors of DEX and autophagy, respectively, were administered before the injection of DEX to examine the protective mechanism of DEX. Results: Pretreatment with DEX ameliorated kidney structure and function. DEX decreased the levels of blood urea nitrogen (BUN) and creatinine (Cre), urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), and apoptosis proteins (such as cleaved caspase-9 and cleaved caspase-3). However, DEX upregulated the levels of autophagy and mitophagy proteins, such as Beclin-1, LC3 II and PINK1. These results suggest that DEX ameliorated LPS-induced AKI by reducing oxidative stress and apoptosis and enhancing autophagy. To promote autophagy, DEX inhibited the phosphorylation levels of PI3K, AKT, and mTOR. Furthermore, the administration of Atip and 3-MA inhibitors blocked the renoprotection effects of DEX. Conclusions: Here, we demonstrate a novel mechanism in which DEX protects against LPS-induced AKI. DEX enhances autophagy, which results in the removal of damaged

show abstract

“…These changes eventually led to microvascular endothelial-alveolar epithelial barrier disruption, neutrophil infiltration, pulmonary edema formation and gas exchange impairment. 6,8 Airway epithelium is continuously considered the first line of host defense against noxious insults. Bundles of studies observed mitochondrial dysfunction of airway epithelial cells (AECs) in ALI/ARDS.…”

Section: Introductionmentioning

confidence: 99%

<p>Mitochondria-Modulating Porous Se@SiO<sub>2</sub> Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

Wang¹,

Wang²,

Deng³

et al. 2020

IJN

View full text Add to dashboard Cite

Background: Mitochondrial dysfunction played a vital role in the pathogenesis of various diseases, including acute lung injury (ALI). However, few strategies targeting mitochondria were developed in treating ALI. Recently, we fabricated a porous Se@SiO 2 nanoparticles (NPs) with antioxidant properties. Methods: The protective effect of Se@SiO 2 NPs was assessed using confocal imaging, immunoblotting, RNA-seq, mitochondrial respiratory chain (MRC) activity assay, and transmission electron microscopy (TEM) in airway epithelial cell line (Beas-2B). The in vivo efficacy of Se@SiO 2 NPs was evaluated in a lipopolysaccharide (LPS)-induced ALI mouse model. Results: This study demonstrated that Se@SiO 2 NPs significantly increased the resistance of airway epithelial cells under oxidative injury and shifted lipopolysaccharide-induced gene expression profile closer to the untreated controls. The cytoprotection of Se@SiO 2 was found to be achieved by maintaining mitochondrial function, activity, and dynamics. In an animal model of ALI, pretreated with the NPs improved mitochondrial dysfunction, thus reducing inflammatory responses and diffuse damage in lung tissues. Additionally, RNA-seq analysis provided evidence for the broad modulatory activity of our Se@SiO 2 NPs in various metabolic disorders and inflammatory diseases. Conclusion: This study brought new insights into mitochondria-targeting bioactive NPs, with application potential in curing ALI or other human mitochondria-related disorders.

show abstract

Mitochondrial quality control mechanisms as potential therapeutic targets in sepsis-induced multiple organ failure

Cited by 60 publications

References 121 publications

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

<p>Mitochondria-Modulating Porous Se@SiO<sub>2</sub> Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

Contact Info

Product

Resources

About