Mitophagy: a balance regulator of NLRP3 inflammasome activation

Kim, Min-Ji; Yoon, Joo Heon; Ryu, Ji Hwan

doi:10.5483/bmbrep.2016.49.10.115

Cited by 141 publications

(116 citation statements)

References 72 publications

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“…Previous studies have reported that mitophagy negatively regulates inflammasome activation and metformin treatment decreases the expression of NLRP3, caspase‐1 and IL‐β in NDT2DM patients . However, our data appeared inconsistent with prior studies and revealed that metformin therapy led to augmented NLRP3 protein expression in these patients, which may subsequently trigger caspase‐1‐mediated pyroptosis of chronically activated macrophages, and thereby impeding chronic inflammation (Figure ).…”

Section: Discussioncontrasting

confidence: 94%

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

Bhansali

Dutta

et al. 2020

J Cellular Molecular Medi

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Impaired mitochondrial autophagy (mitophagy) and NLRP3 inflammasome activation have been incriminated in the pathogenesis of T2DM. Metformin besides being an insulin sensitizer also induces autophagy; however, its effect on mitophagy and NLRP3 activation in patients with T2DM still remains elusive. Forty‐five drug‐naïve T2DM patients with HbA1C 7%‐9% (53‐75 mmol/mol) were randomly assigned to receive either metformin, voglibose, or placebo for 3 months, and were also recommended for lifestyle intervention programme (n = 15 each). Mitochondrial oxidative stress (MOS) parameters, qPCR and immunoblotting of mitophagy‐related markers (PINK1, PARKIN, MFN2, NIX, LC3‐II, LAMP2), p‐AMPKα (T172), and NLRP3 proteins, as well as transmission electron microscopy (TEM) for assessing mitochondrial morphology were performed in the mononuclear cells of study patients. Both metformin and voglibose showed a similar efficacy towards the reduction in HbA1c and MOS indices. However, multivariate ANCOVA divulged that mRNA and protein expression of mitophagy markers, NLRP3 and p‐AMPKα (T172), were significantly increased only with metformin therapy. Moreover, PINK1 expression displayed a significant positive association with HOMA‐β indices, and TEM studies further confirmed reduced distortions in mitochondrial morphology in the metformin group only. Our observations underscore that metformin upregulates mitophagy and subsequently ameliorates the altered mitochondrial morphology and function, independent of its glucose‐lowering effect. Further, restoration of normal mitochondrial phenotype may improve cellular function, including β‐cells, which may prevent further worsening of hyperglycaemia in patients with T2DM.

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Section: Discussioncontrasting

confidence: 94%

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

Bhansali

Dutta

et al. 2020

J Cellular Molecular Medi

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“…Mitophagy, a mitochondria‐specific autophagy pathway, has been reported to be a negative regulator of NLRP3 inflammasome‐mediated hyperinflammation . Mounting evidence suggests that mitophagy and disruption of mitochondrial dynamics directly contribute to dopaminergic neuronal cell death in PD .…”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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“…However, there is still a lack of drugs that directly interfere with NLRP3 inflammasome activation in clinical treatment. In addition, in LPS-primed macrophages, the interaction between endogenous ABRO1 and NLRP3 disappeared upon nigericin or ATP stimulation, implying that this key molecular mechanism of NLRP3 deubiquitination mediated by ABRO1 may contribute to the self-limiting regulation of inflammasome activation (Kim et al, 2016). Importantly, various DUBs are emerging as attractive therapeutic targets in diseases ranging from oncology to neurodegeneration, and firstgeneration DUB inhibitors are now approaching clinical trials (Harrigan et al, 2018).…”

Section: Of 17mentioning

confidence: 99%

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

et al. 2019

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Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3‐ASC complex formation, ASC oligomerization, caspase‐1 activation, and IL‐1β and IL‐18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3‐associated inflammatory diseases, including MSU‐ and Alum‐induced peritonitis and LPS‐induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation‐dependent manner, subsequently recruiting the BRISC to remove K63‐linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active component of BRISC, displays similar phenotypes to ABRO1 knockout mice. Our findings reveal an ABRO1‐mediated regulatory signaling system that controls activation of the NLRP3 inflammasome and provide novel potential targets for treating NLRP3‐associated inflammatory diseases.

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Mitophagy: a balance regulator of NLRP3 inflammasome activation

Cited by 141 publications

References 72 publications

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

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