Mitochondria-meditated pathways of organ failure upon inflammation

Abstract

Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca²⁺ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca⁺⁺ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca²⁺ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.

Keywords: Inflammation; Liver failure; Mitochondria; Reactive oxygen species; Signaling.

Graphical abstract

Fig. 1

Mitochondrial ROS-signaling in liver cells upon acute inflammation. Pro-inflammatory mediators (e.g. TNFα) decrease ATP levels and activate mtROS production, but do not control directly the release of mtROS in cytoplasm. Anti-inflammatory mediators (e.g. IL-4) decrease mtROS generation. The release of mtROS via mPTP is controlled by Ca²⁺, and ROS originated from both mitochondria and NOX. In addition, pro-inflammatory mediators shift the Bcl/Bax balance in the direction of apoptosis, but the execution of apoptosis is inhibited by low levels of ATP in hepatocytes. Simultaneously, pro-inflammatory mediators up-regulate iNOS thereby increasing NO levels, which activates feed forward loop including mtROS and iNOS. This loop may also induce oxidative stress if NO and ROS are generated in a great excess. Another feed forward loop includes mtROS and NOX, the latter further accelerates both mtROS production and NOX activity. Abbreviations: AIF–apoptosis inducing factor, ATP–adenosine triphosphate, Bax–B-cell lymphoma-associated X protein, c-Src–cellular sarcoma, cyt c–cytochrome c, ER–endoplasmic reticulum; IL–interleukin; INF–interferon; iNOS–inducible nitric oxide synthase, JNK–c-Jun N-terminal kinase, mitoK_ATP–adenosine triphosphate sensitive potassium channel, mPTP–mitochondrial permeability transition pore, NO–nitric oxide, NOX–NADPH-oxidase, R_anti-IM–receptors for anti-inflammatory mediators, O₂–molecular oxygen, PKC–protein kinase C, ROS–reactive oxygen species, R_pro-IM–receptors for pro-inflammatory mediators, STAT-signal transducer and activator of transcription, TNF–tumor necrosis factor, Δψ–membrane potential, I-IV–complexes I-IV of electron transport chain.

Fig. 2

Interaction of regulatory factors with ATP and ROS production of the mitochondrial electron transport chain. At least three major signaling pathways (STAT3, JNK and NO) regulate mtROS production under acute inflammation. Signal transducer and activator of transcription protein 3 is activated by phosphorylation by Janus Kinase (JAK) proteins. After phosphorylation, STAT3 binds directly to GRIM-19, a subunit of mitochondrial ETC complex I, and is then transported into mitochondria, where it enhances activity of complex I, thereby enhancing ATP synthesis, and reduces ROS production. Phosphorylated JNK1/2 forms a complex in the outer mitochondrial membrane with MKK4, Bax and Sab. Then, this signal will be transmitted to the inner mitochondrial membrane by SHP1, which decreases complex IV protein phosphorylation causing a decrease in ATP synthesis and an increase in ROS production. As a third pathway, nitric oxide and peroxynitrite are able to directly inhibit complex I and IV causing a drop in ATP levels, and increase ROS formation. Abbreviations: ATP–adenosine triphosphate, Bax– B-cell lymphoma-associated X protein, cyt c–cytochrome c, GRIM-19–gene associated with retinoid interferon induced cell mortality 19, H₂O₂–hydrogen peroxide, IMM–inner mitochondrial membrane, IMS–intermembrane space, JNK–cJun N-terminal kinase, MKK–mitogen-activated protein kinase kinase, NO–nitric oxide, ONOO–peroxynitrite, O₂^•-–superoxide radical, O₂–molecular oxygen, OMM–outer mitochondrial membrane, Q–Q-cycle, Sab–SH3BP5, STAT–signal transducer and activator of transcription, CI-CV–mitochondrial electron transport chain complex I–V.

Fig. 3

Mechanism regulating reactive oxygen species release into cytoplasm. Under normal conditions, mPTP is impermeable (A). Under inflammatory and other pathologic conditions, two pathways are repeatedly described in the literature. The first one is ROS-dependent ROS release (B). Elevated ROS levels facilitate oxidation of cysteines at different sites of mitochondrial F-ATP synthase. The first, called S-site, is associated with the voltage sensor of the mPTP. The second, termed as “P-site”, can be affected by oxidation-reduction state of pyridine nucleotides. An additional site is located on the outer surface of the inner mitochondrial membrane (here indicated as “O”) which can modulate the mPTP opening in a two-step reaction. The second mechanism is Ca++-dependent (C). Increased concentrations of Ca++ and cyclophilin D convert the F-ATP synthase to a non-specific pore which facilitates the release of ROS from mitochondria to the cytosol. Phosphorylated STAT3 can inhibit the opening of the mitochondrial permeability transition pore by binding to Cyp D. Abbreviations: ATP—adenosine triphosphate, Cyp D—cyclophilin D, ROS—reactive oxygen species.

Fig. 4

Mechanism of ROS-mediated signaling pathways in cytoplasm. Upon inflammation, ROS predominantly activate two kinases, PKC and c-Src. Under normal conditions, PKC is kept in an inactive “closed” configuration. The zinc finger at the regulatory unit, a complex between SH groups and zinc atoms, defines this configuration, which does not allow phosphorylation. ROS can interact with SH groups, thereby disrupting this binding. This results in the release of zinc (A) and activation (B) of PKC. Similar to PKC, c-Src is inactive under normal conditions. In this catalytically inactive conformation, the kinase domain of c-Src interacts with the SH2-domain (C). The activation of c-Src may occur through S-nitrosylation of cysteine 498 of kinase domain by NO (D) or intermolecular disulfide bond formation between cysteine 245 and cysteine 487 by ROS (E). ROS oxidize these SH groups linking catalytic domain and SH2 by means of S-S bridge (E). Abbreviations: cat—catalytic subunit, cys—cysteine, H₂O₂—hydrogen peroxide, NO—nitric oxide, reg—regulatory subunit, SH—Src homolog.