Mitophagy Contributes to the Pathogenesis of Inflammatory Diseases

Zhao, Yan; Huang, Shao Mei; Liu, Jie; Wu, Ximing; Zhou, Shuai; Dai, Ke; Kou, Yurong

doi:10.1007/s10753-018-0835-2

Cited by 58 publications

(42 citation statements)

References 83 publications

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“…Atg12-deficient or Lc3a −/− Lc3b −/− macrophages contained more damaged mitochondria than wild-type cells in response to LPS plus ATP stimulation as previously reported (45). The accumulation of damaged mitochondria is caused by an impairment in autophagy termed mitophagy due to lack of Atg12 or LC3s (57). In contrast, the formation of GBP2 aggregates due to lack of Gate-16 and Gabarap is the direct cause of caspase-11 over-activation and is independent of autophagy because GBP aggregation was observed only in cells lacking Atg3, Atg5, Atg7, or Atg16L1, all of which are essential for Atg8 lipidation, but not in cells lacking Atg9, Atg14, or FIP200, all of which are essential for autophagy (39,42).…”

Section: Discussionsupporting

confidence: 73%

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

et al. 2020

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Sepsis is a life-threating multi-organ disease induced by host innate immunity to pathogen-derived endotoxins including lipopolysaccharide (LPS). Direct sensing of LPS by caspase-11 activates inflammasomes and causes lethal sepsis in mice. Inhibition of caspase-11 inflammasomes is important for the prevention of LPS-induced septic shock; however, whether a caspase-11 inflammasome-specific suppressive mechanism exists is unclear. Here we show that deficiency of GABARAP autophagy-related proteins results in over-activation of caspase-11 inflammasomes but not of canonical inflammasomes. Gate-16 −/− Gabarap −/− macrophages exhibited elevated guanylate binding protein 2 (GBP2)-dependent caspase-11 activation and inflammatory responses. Deficiency of GABARAPs resulted in formation of GBP2-containing aggregates that promote IL-1β production. High mortality after low dose LPS challenge in Gate-16 −/− Gabarap −/− mice primed with poly(I:C) or polymicrobial sepsis was ameliorated by compound GBP2 deficiency. These results reveal a critical function of Gate-16 and Gabarap to suppress GBP2-dependent caspase-11-induced inflammation and septic shock.

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Section: Discussionsupporting

confidence: 73%

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

et al. 2020

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“…MD plays an important role in several diseases, including AKI [19,29,30]. Additionally, MD is often associated with the triggering of mitophagy pathways, which eliminate dysfunctional or impaired mitochondria [6,31]. Therefore, in the present study, we investigated whether Parkin-mediated mitophagy participates in PD-induced protection against SI-AKI via its effect on MD.…”

Section: Discussionmentioning

confidence: 96%

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Gao

Dai

et al. 2020

J Transl Med

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Background: We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsisinduced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. Methods: Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. Key results: PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin−/− mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkindependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. Conclusions: These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

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“…We investigated the potential molecular mechanisms involved in BBR‐mediated mitophagy induction. Three mechanisms of mitophagy have been extensively investigated, namely, BNIP3‐related mitophagy, PTEN‐induced kinase 1 (PINK1)/Parkin pathway‐related mitophagy, and FUN14 domain‐containing 1 (FUNDC1)‐mediated mitophagy 50 . In our study, we focused on BNIP3‐mediated mitophagy.…”

Section: Discussionmentioning

confidence: 99%

Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

Liu

You

et al. 2020

Journal of Leukocyte Biology

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Berberine (BBR) is an isoquinoline alkaloid extracted from several commonly used Chinese herbs. Our previous studies demonstrated BBR‐mediated alleviation of lung injury due to inflammation and decrease in the mortality of mice with influenza viral pneumonia. The recent argument of autophagy against inflammatory responses has aroused wide concerns. This study focuses on the reactive oxygen species‐Nod‐like receptor protein 3 (ROS‐NLRP3) pathway to investigate whether BBR inhibits NLRP3 inflammasome activation by inducing mitophagy. Our results demonstrate that BBR and mitochondrion‐targeted superoxide dismutase mimetic (Mito‐TEMPO; a specific mitochondrial ROS scavenger) significantly restricted NLRP3 inflammasome activation, increased mitochondrial membrane potential (MMP), and decreased mitochondrial ROS (mtROS) generation in J774A.1 macrophages infected with PR8 influenza virus. These observations suggest that the inhibitory effects of BBR on NLRP3 inflammasome activation were associated with the amelioration of mtROS generation. BBR treatment induced regular mitophagy, as evident from the increase in microtubule‐associated protein 1 light chain 3 II, decrease in p62, colocalization of LC3 and mitochondria, and formation of autophagosomes. However, 3‐methyladenine, an autophagy inhibitor, reversed the inhibitory effects of BBR on mitochondrial damage and NLRP3 inflammasome activation in influenza virus‐infected macrophages, indicating the involvement of mitophagy in mediating the inhibitory effects of BBR on NLRP3 inflammasome activation. Furthermore, the knockdown of Bcl‐2/adenovirus E18‐19‐kDa interacting protein 3 (BNIP3) expression attenuated the effects of BBR on mitophagy induction to some extent, suggesting that the BBR‐induced mitophagy may be, at least in part, mediated in a BNIP3‐dependent manner. Similar results were obtained in vivo using a mouse model of influenza viral pneumonia that was administered with BBR. Taken together, these findings suggest that restricting NLRP3 inflammasome activation by decreasing ROS generation through mitophagy induction may be crucial for the BBR‐mediated alleviation of influenza virus‐induced inflammatory lesions.

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Mitophagy Contributes to the Pathogenesis of Inflammatory Diseases

Cited by 58 publications

References 83 publications

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

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