Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model

Qiu, Jingru; Chen, Ye; Zhuo, Jing; Zhang, Li; Liu, Jia; Wang, Baozhu; Sun, Deqing; Yu, Shu; Lou, Haiyan

doi:10.1016/j.neuropharm.2022.108963

Cited by 80 publications

(60 citation statements)

References 36 publications

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“…Mitophagy enhancement via genetic approaches or small molecules was shown to relieve mtROS accumulation and mtDNA release and, more importantly, inhibit the secretion of inflammatory factors in vitro and in vivo ( Suen et al, 2010 ; Sliter et al, 2018 ; Fang et al, 2019b ; Qiu et al, 2022 ). Conversely, autophagy-deficient macrophages showed an accumulation of defective mitochondria, accompanied by NLRP3 activation and IL-1β secretion ( Saitoh et al, 2008 ; Nakahira et al, 2011 ).…”

Section: Mitophagy and Innate Immunitymentioning

confidence: 99%

Roles of microglial mitophagy in neurological disorders

Liu

Wang

Hou

et al. 2022

Front. Aging Neurosci.

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Microglia are the resident innate immune cells in the central nervous system (CNS) that serve as the first line innate immunity in response to pathogen invasion, ischemia and other pathological stimuli. Once activated, they rapidly release a variety of inflammatory cytokines and phagocytose pathogens or cell debris (termed neuroinflammation), which is beneficial for maintaining brain homeostasis if appropriately activated. However, excessive or uncontrolled neuroinflammation may damage neurons and exacerbate the pathologies in neurological disorders. Microglia are highly dynamic cells, dependent on energy supply from mitochondria. Moreover, dysfunctional mitochondria can serve as a signaling platform to facilitate innate immune responses in microglia. Mitophagy is a means of clearing damaged or redundant mitochondria, playing a critical role in the quality control of mitochondrial homeostasis and turnover. Mounting evidence has shown that mitophagy not only limits the inflammatory response in microglia but also affects their phagocytosis, whereas mitochondria dysfunction and mitophagy defects are associated with aging and neurological disorders. Therefore, targeting microglial mitophagy is a promising therapeutic strategy for neurological disorders. This article reviews and highlights the role and regulation of mitophagy in microglia in neurological conditions, and the research progress in manipulating microglial mitophagy and future directions in this field are also discussed.

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Section: Mitophagy and Innate Immunitymentioning

confidence: 99%

Roles of microglial mitophagy in neurological disorders

Liu

Wang

Hou

et al. 2022

Front. Aging Neurosci.

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“…As mentioned previously, induction of mitophagy via small molecules such as urolithin A, rescues cellular and behavioral phenotypes in multiple neurodegenerative disease models. Interestingly, urolithin A also inhibited multiple tau phosphorylation sites in AD mouse models ( Liu et al, 2018 , 2022 ; Kujawska et al, 2020 ; Qiu et al, 2022 ). Restoration of mitophagy via overexpression of PINK1 was also associated with neuroprotective effects in Drosophila models of HD ( Khalil et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, treatment with urolithin A, which promotes mitophagy, recovers mitochondrial function and motor deficits in the 6-OHDA treated PD mouse model. Urolithin A promotes mitochondrial biogenesis via the SIRT1-PGC-1α pathway and attenuates the inflammatory response in microglia by inhibiting NLRP3 inflammasome activation ( Kujawska et al, 2020 ; Liu et al, 2022 ; Qiu et al, 2022 ). These findings again pointing to the dysregulation of mitochondrial dynamics and clearance as prominent causes of PD pathology.…”

Section: Mitochondrial Quality Control Mechanisms In Proteinopathiesmentioning

confidence: 99%

Altered Mitochondrial Protein Homeostasis and Proteinopathies

Jishi

2022

Front. Mol. Neurosci.

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Increasing evidence implicates mitochondrial dysfunction as key in the development and progression of various forms of neurodegeneration. The multitude of functions carried out by mitochondria necessitates a tight regulation of protein import, dynamics, and turnover; this regulation is achieved via several, often overlapping pathways that function at different levels. The development of several major neurodegenerative diseases is associated with dysregulation of these pathways, and growing evidence suggests direct interactions between some pathogenic proteins and mitochondria. When these pathways are compromised, so is mitochondrial function, and the resulting deficits in bioenergetics, trafficking, and mitophagy can exacerbate pathogenic processes. In this review, we provide an overview of the regulatory mechanisms employed by mitochondria to maintain protein homeostasis and discuss the failure of these mechanisms in the context of several major proteinopathies.

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“…In turn, activated glial cells release inflammatory factors, triggering cellular cascades, which can exacerbate mitochondrial damage, triggering and intensifying a vicious circle between neuroinflammation and mitochondrial dysfunction, which finally results in NDD. Notably, mitochondrial quality control by mitophagy is a crucial intrinsic response to prevent neuroinflammation, by limiting mtDNA and mtROS release from damaged mitochondria, and NLRP3 inflammasome activation [ 234 , 235 , 236 , 237 ].…”

Section: Neuroprotective Potential Of β-Caryophyllene and Carnosic Ac...mentioning

confidence: 99%

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

2022

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Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

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Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model

Cited by 80 publications

References 36 publications

Roles of microglial mitophagy in neurological disorders

Roles of microglial mitophagy in neurological disorders

Altered Mitochondrial Protein Homeostasis and Proteinopathies

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

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