Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response

Abstract

Mitochondria, the dynamic organelles and power house of eukaryotic cells function as metabolic hubs of cells undergoing continuous cycles of fusion and fission. Recent findings have made it increasingly apparent that mitochondria essentially involved in energy production have evolved as principal intracellular signaling platforms regulating not only innate immunity but also inflammatory responses. Perturbations in mitochondrial dynamics, including fusion/fission, electron transport chain (ETC) architecture and cristae organization have now been actively correlated to modulate metabolic activity and immune function of innate and adaptive immune cells. Several newly identified mitochondrial proteins in mitochondrial outer membrane such as mitochondrial antiviral signaling protein (MAVS) and with mitochondrial DNA acting as danger-associated molecular pattern (DAMP) and mitochondrial ROS generated from mitochondrial sources have potentially established mitochondria as key signaling platforms in antiviral immunity in vertebrates and thereby orchestrating adaptive immune cell activations respectively. A thorough understanding of emerging and intervening role of mitochondria in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation has gained lucidity in recent years that advocates the imposing functions of mitochondria in innate immunity. Fascinatingly, also how the signals stemming from the endoplasmic reticulum co-operate with the mitochondria to activate the NLRP3 inflammasome is now looked ahead as a stage to unravel as to how different mitochondrial and associated organelle stress responses co-operate to bring about inflammatory consequences. This has also opened avenues of research for revealing mitochondrial targets that could be exploited for development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders. Thus, this review explores our current understanding of intricate interplay between mitochondria and other cellular processes like autophagy in controlling mitochondrial homeostasis and regulation of innate immunity and inflammatory responses.

Keywords: Inflammasome; Inflammation; Innate immune response; Mitochondrial dynamics; Mitophagy; NLRP3.

Fig. 1

Mitochondrial dynamics regulate T cell immunity and MAVS mediated antiviral signaling. a: The memory cells (T_m cells) show fused phenotype with elongated mitochondria expressing fusion proteins, MFN1, MFN2 and OPA1 resulting in tight cristae mediated efficient ETC super complex formation and OXPHOS whereas the effector T cells (T_eff cells) are characterized by fragmented mitochondria with loose cristae and disrupted ETC complex and inefficient OXPHOS thus shifting the metabolism towards aerobic glycolysis. Naïve T cells show fragmented, small round mitochondria with low mitochondrial membrane potential (Δψ_m) that blocks the signaling by NF-κΒ and IRF-3. (Refer to left side of Fig. 1). b: During viral infection, mitochondrial antiviral signaling protein (MAVS)-enriched mitochondria surround the viral replication center to promote RLR mediated MAVS signaling .The mitofusins, MFN1 and MFN2 orchestrate the fusion of mitochondrial network with endoplasmic reticulum (ER)-localized MFN2 that further stimulates the interaction between MAVS and STING (stimulator of interferon genes protein) at mitochondria-associated membranes (MAMs). Interestingly, the mitochondrial MAVS triggers both IFN-β and IFN-λ production while the peroxisomal MAVS induces IFN-λ secretion in an interferon regulatory factor 1 (IRF1) dependent manner. (Refer to right side of Fig. 1)