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

• Published in: The international journal of biochemistry & cell biology 2021-07, Vol.136, p.106013-106013, Article 106013
• Main Authors: Mishra, Soumya Ranjan, Mahapatra, Kewal Kumar, Behera, Bishnu Prasad, Patra, Srimanta, Bhol, Chandra Sekhar, Panigrahi, Debasna Pritimanjari, Praharaj, Prakash Priyadarshi, Singh, Amruta, Patil, Shankargouda, Dhiman, Rohan, Bhutia, Sujit Kumar
• Format: Article
• Language: English
• Subjects: Inflammasome; Mitochondria; Mitochondrial dynamics; Mitophagy; NLRP3
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2021.106013

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.