Mitochondrial dysfunction as a driver of NLRP3 inflammasome activation and its modulation through mitophagy for potential therapeutics

May 22, 2021The international journal of biochemistry & cell biology

Mitochondrial problems may trigger inflammation through NLRP3 and can be controlled by removing damaged mitochondria for possible treatments

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Abstract

The NLRP3 inflammasome is implicated in neuroinflammation and neural diseases.

NLRP3 inflammasome activation occurs in response to various stimuli, including microbial infections and protein aggregates.
Activation of the NLRP3 inflammasome triggers caspase-1, leading to the release of inflammatory cytokines like interleukin-1β and interleukin-18.
Mitochondrial dysfunction contributes to NLRP3 inflammasome activation through the accumulation of reactive oxygen species and mitochondrial DNA.
Imbalances in mitochondrial dynamics, such as fission and fusion, can promote NLRP3 inflammasome activation.
Mitophagy plays a critical role in maintaining mitochondrial health and may limit NLRP3 inflammasome hyperactivation.
Identifying novel mitophagy modulators may offer therapeutic strategies for neuronal diseases linked to NLRP3 inflammasome activation.

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The NLR family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the sensation of various pathogenic and non-pathogenic damage signals and has a vital role in neuroinflammation and neural diseases. Various stimuli, such as microbial infection, misfolded protein aggregates, and aberrant deposition of proteins can induce NLRP3 inflammasome in neural cells. Once triggered, the NLRP3 inflammasome leads to the activation of caspase-1, which in turn activates inflammatory cytokines, such as interleukin-1β and interleukin -18, and induces pyroptotic cell death. Mitochondria are critically involved in diverse cellular processes and are involved in regulating cellular redox status, calcium levels, inflammasome activation, and cell death. Mitochondrial dysfunction and subsequent accumulation of mitochondrial reactive oxygen species, mitochondrial deoxyribonucleic acid, and other mitochondria-associated proteins and lipids play vital roles in the instigation of the NLRP3 inflammasome. In addition, the processes of mitochondrial dynamics, such as fission and fusion, are essential in the maintenance of mitochondrial integrity and their imbalance also promotes NLRP3 inflammasome activation. In this connection, mitophagy-mediated maintenance of mitochondrial homeostasis restricts NLRP3 inflammasome hyperactivation and its consequences in various neurological disorders. Hence, mitophagy can be exploited as a potential strategy to target damaged mitochondria induced NLRP3 inflammasome activation and its lethal consequences. Therefore, the identification of novel mitophagy modulators has promising therapeutic potential for NLRP3 inflammasome-associated neuronal diseases.

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Mitochondrial dysfunction as a driver of NLRP3 inflammasome activation and its modulation through mitophagy for potential therapeutics

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