Mitochondrial Oxidative Stress and "Mito-Inflammation": Actors in the Diseases

Abstract

A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

Keywords: cancer; diabetes; gastrointestinal disorders; mito-inflammation; mitochondria; neurodegenerative disorders; oxidative stress; pulmonary diseases.

Figure 1

Mitochondrial sites of ROS production. Mitochondrial complex I and III of respiratory chain are the principal sites of O₂^•− production within a cell, which can be converted to H₂O₂ by superoxide dismutase (SOD1 and SOD2) enzymes. H₂O₂ in turn is rapid neutralized to H₂O and oxygen by glutathione peroxidase (GPX). However, other mitochondrial proteins, localized from OMM to matrix, may also contribute to mtROS production, including monoamine oxidase A and B (MAO A/B), cytochrome (Cyt.) b5 reductase, mitochondrial glycerol-phosphate dehydrogenase (mGPDH), p66Shc, Fhit with ferredoxin reductase (FDxR), adrenodoxin reductase (ADxR)-adrenodoxin (ADX)-cytochrome P450scc (CYP450) system, α-ketoglutharate dehydrogenases (KGDHC), acyl-CoA dehydrogenases (ACAD) and aconitase. This figure has been created with “BioRender.com.”.

Figure 2

Mitochondrial ROS-induced inflammatory response. Representation of multifaceted aspects of mitochondrial ROS in inflammation. Increased mtROS cause oxidative damage to mitochondrial membrane, with events of lipidic peroxidation and changes in membrane permeability, molecules, proteins, and mtDNA, which contribute to mitochondrial dysfunction and exacerbation of mtROS production. The dissemination of mtROS actives the redox-sensitive transcription factor NF-kB, inducing the expression of inflammasome genes, such as Nlrp3, Nlrc4, and Il1b genes. In turn, the mtROS and mtDNA promote the cytokines release mediating the inflammasome NLRP3 and NLRC4 complex activation, through the recruitment of pro-caspase−1 and the processing of pro-IL−1 and pro-IL−18. Finally, mtROS are reversed to extracellular milieu to sustain and exacerbate the inflammatory responses, affecting proximal cells and conditioning the inflammatory microenvironment. Abbreviations: Reactive oxygen species, ROS; Interleukin−18, IL−18; Interleukin−1, IL−1; NLR Family CARD Domain Containing 4, NLRC4; ASC; NLR Family Pyrin Domain Containing 3, NLRP3; Mitochondrial antiviral-signaling protein, MAVS; mitochondrial deoxyribonucleic acid, mtDNA; NLR Family member X1 precursor, NLRX1; Calcium, Ca²⁺; Nuclear factor kappa-light-chain-enhancer of activated B cells, NF-kB; Mitochondrial membrane potential, ΔΨ. This figure has been created with “BioRender.com.”.