Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation

Abstract

Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.

Keywords: dermatomyositis; inflammation; mitochondria; myositis; reactive oxygen species; rheumatoid arthritis; systemic lupus erythematosus.

Figure 1

Mitochondria are a platform for pattern recognition receptors (PRRs) signal transduction and regulation. In intact cells, intracellular signaling pathways of several critical PRRs physically interact with mitochondria to act as a modulator. RIG-I-like receptors (RLRs) (retinoic acid- inducible gene I and melanoma differentiation-associated protein 5 MDA5) signals are dependent of MAVS, the activation of which (oligomerization) is enhanced by mtROS and mitochondrial fusion [regulated by mitofusin (MFN) 1 and MFN2]. NLRP3-inflammasome assembly also interacts with MAVS for proper activation. Moreover, mtROS and several mtDAMPs activate the NLRP3-inflammasome (see Figure 2). Toll-like receptor (TLR) 1, TLR2, and TLR4 ligation leads to the enrichment of TRAF6 and Evolutionarily Conserved Signaling Intermediate In Toll Pathway (ECSIT) (a complex I–assembly factor) at the mitochondrial periphery and subsequent recruitment of mitochondria to macrophage phagosomes were they produce mtROS. TLR7 signaling involves the mitochondrial protein membrane-associated ring-CH-type finger 5 (MARCH5), which catalyzes the polyubiquitination and degradation of TANK a repressor of TLR7 signaling pathway.

Figure 2

Mitochondrial components act as damage-associated molecular patterns (DAMPS). (A) In stressed cells [e.g., viral infection, defect of autophagy, toll-like receptors (TLRs) ligation], mitochondrial transition pore (MPTP) opening extrudes several mitochondrial components in the cytoplasm where they activate pattern recognition receptors (PRRs). Mitochondrial DNA (mtDNA) activates cyclic GMP–AMP synthase (cGAS) receptor and NLRP3 inflammasome. Cardiolipin and mtROS trigger NLRP3 inflammasome. (B) Damaged cells release mitochondrial DAMPs into the extracellular milieu where they stimulate PRRs harbored by macrophages and neutrophils. Adenosine triphosphate (ATP) leads to P2X7 opening at the macrophage membrane and triggers NLRP3 inflammasome. mtDNA unmethylated CpG motifs are recognized by TLR9. N-formylmethionine residues in mitochondrial proteins are sensed by the formyl-peptide receptors expressed by neutrophils, driving chemotactism and activation of these cells.