Abstract
Abstract
Introduction Sepsis-induced myocardial dysfunction (SIMD) is a condition manifested by an intrinsic myocardial systolic and diastolic dysfunction during sepsis, which is associated with worse clinical outcomes and a higher mortality.
Materials and methods Several pathophysiological mechanisms including mitochondrial dysfunction, abnormal body immune reaction, metabolic reprogramming, excessive production of reactive oxygen species (ROS), and disorder of calcium regulation have been involved in SIMD. Mitophagy has potential role in protecting myocardial cells in sepsis, especially in survivors.
Conclusion In the current review, we focus on the role of mitochondrial dysfunction and other mitochondria-related mechanisms including immunologic imbalance, energetic reprogramming, mitophagy, and pyroptosis in the mechanisms of SIMD.
Keywords: Sepsis-induced myocardial dysfunction · Mitochondrial dysfunction · Lactate · Immunosuppression
Introduction
Introduction
SIMD is defined as a reversible myocardial dysfunction characterized by typical ventricular dilation, decreased ventricular contractility, and/or reduced response to volume resuscitation. SIMD is a major complication of sepsis and has a negative impact on patients’ survivals. Evidence suggests several mechanisms and signal pathways. Mitochondrial dysfunction has become a serious concern, including oxidative phosphorylation, production of ROS, reprogramming metabolism of energy, and mitophagy. And body’s immune reaction changes may also play a potential role in SIMD. Previous research has also shown other factors are associated with SIMD including altered epigenetic modification, myocardial depressant factors, pathogen-associated molecular patterns (PAMPs), host-produced danger-associated molecular patterns (DAMPs), high-mobility group box 1 (HMBG1), and activated complement components. In addition, the role of pro-inflammatory cytokines, decreased coronary perfusion, and altered microcirculation in the presence of severe hypotension during sepsis can also lead to myocardial hypoxia and dysfunction. In this article, the potential role of mitochondria in the mechanism of SIMD will be reviewed.
Mitochondrial permeability transition pore (mPTP) is proposed as a high-conductance channel of the almost impermeable inner mitochondrial membrane (IMM). Physiologically, it serves as a rapid mitochondrial efflux channel for ROS and Ca2+ via a transient opening. Its abnormal opening can increase the IMM permeability and change the membrane potential of the mitochondria, leading to a reduction of the electrochemical transmembrane gradient, uncoupling of oxidative phosphorylation, increasing production of ROS, and decreasing production of ATP. Furthermore, the c-ring of the F1F0-ATP synthase has been demonstrated as a component of mPTP and might directly influence ATP synthase. In addition, mPTP is tightly associated with cell apoptosis. When outer mitochondrial membrane (OMM) ruptures, N-formyl peptides, ATP, and cytochrome C are released, and cellular ATP is depleted after the irreversible opening of mPTP, which can be initiated by calcium retention, a central stimulator. Besides the calcium concentration, pH, ROS, nitric oxide (NO) production in excess, peroxynitrite formed from NO can affect the function of mPTP. An mPTP opening was observed in the swelling mitochondria. Multiple mPTP inhibitors have demonstrated efficacy in preclinical disease models. However, although mPTP is involved in cell damage and death, SIMD lacks cell necrosis or apoptosis probably associated with the severity of sepsis. This also indicates that the opening of mPTP is properly functioning, when myocardial cells suffer from deteriorating sepsis (Fig. 1).
The dysregulation of mitochondrial calcium was observed in the case of sepsis. In myocardial cells, the homeostasis of calcium is both cytoplasmic and mitochondrial. Mitochondrial Ca2+ channels in IMM include mitochondrial Ca2+ uniporter (MCU), mitochondrial ryanodine receptor (mRyR), mPTP, mitochondrial Na+/Ca2+ exchanger (mNCX), and H+/Ca2+ exchanger (mHCX). MCU is dependent on the IMM potential, associated with the matrix calcium and extramitochondrial Ca2+ concentration. It contributes to oxidative phosphorylation and activates the dehydrogenase of the TCA cycle to increase the production of NADH for electron transport chain (ETC) and ATP generation. Voltage-dependent anion channel (VDAC), a part of mPTP, provides a pathway for Ca2+ and metabolite transportation across OMM. In addition, approximately 20% of the mitochondrial surface has been found to be close to the endoplasmic reticulum in mammalian cells generating high Ca2+ microdomains, termed as mitochondria-associated membranes (MAMs). When the calcium-induced calcium release (CICR) is activated by autonomic nervous system, a considerable amount of calcium is released from ER via RyR, and calcium flows into mitochondria through VDAC in OMM. Thereafter, sarcoplasmic reticulum Ca2+ ATPase (SERCA) reabsorbs calcium to prevent cytoplastic overload, which is a determinant of calcium homeostasis. Tumor suppressor p53 localized in ER can interact with SERCA and exert its pro-apoptotic function by regulating the transporting calcium into mitochondria. An anti-apoptotic member of the Bcl-2 family has been suggested to interact with VDAC and protect cells from death by limiting the transfer of Ca2+ signals to mitochondria. Although calcium overload has been widely shown in septic models which can be via Ca2+ channels mentioned above, little necrosis has been observed in survivors, compared with autophagy which are mediated by mitochondria. In mice, autophagy could play a protective role against pressure-overload-induced mitochondrial dysfunction and heart failure via regulating Drp1. Upregulation of autophagy via activation of SIRT1 could protected against SIMD. Therefore, calcium overload and necrosis may occur via Ca2+ channels mentioned above, but not be the first and appropriate choice in survivors, as the balance of apoptosis via apoptotic member interacting with Ca2+ channels would be kept and autophagy would be activated to protect mitochondria and myocardial cells (Fig. 1).
Sepsis can cause cardiac mitochondrial damage by increasing oxidative stress and decreasing antioxidant defense, causing mitochondrial ROS (mtROS) overproduction, further mitochondrial functional deficiency, and structural rupture due to direct oxidation. The scavenging of mtROS can be achieved via enzymatic and non-enzymatic antioxidants, such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). The accumulation of ROS can lead to more electron leakage after damaging ETC, activation of poly ADP-ribose polymerase (PARP) after damaging mtDNA, and opening of mPTP. It can also cause decreasing oxygen consumption and ATP production, decreasing mitochondrial membrane potential and activity, and decreasing expression of respiratory complexe. Evidence suggested the suppression of mtROS protected cardiac mitochondria, attenuated inflammation, and improved heart function in the animal models of sepsis. The electron leakage depends on the ATP demand. Some models showed that mitochondria-targeted ROS scavengers such as mitochondrial Q was cardioprotective. The anaesthetic agent propofol manifested its cardioprotective effect by scavenging free radical. Clinical therapeutic effects of some typical antioxidants such as vitamin C, vitamin E, and SOD were conflicting. Vitamin B and C combined with corticosteroid in sepsis has been suggested as a promising therapy but currently lacks robust evidence to support its widespread use. NOX inhibitors were also indicated to selectively attenuate disease-related ROS formation without altering physiological signaling ROS. The myocardial cells switch their metabolism to aerobic glycolysis leading to the reduction of the ATP generation. It is reasonable to hypothesize that glycolysis increases and oxidative phosphorylation decreases, contributing to decreasing production of mtROS and reduce the damage from mtROS to mitochondria and cells. Glycolysis can be initiated by hypoxia during sepsis. Theoretically, TCA cycle will decrease and the production of mtROS will correspondingly decrease. Further in this way, damage from mtROS to mitochondria will be alleviated, especially ETC which is prone to mtROS. It may also indicate self-protection of mitochondria is initiated when exposed to sepsis, as continuous impairment of mitochondria including ETC can induce NLRP3 inflammasome. On the other hand, there is a tightly association between mitochondrial energy metabolism and mitochondrial dynamics. As it was known that, LPS-induced M1 macrophages could reprogram their energetic metabolism to glycolysis during infection to afford the energy need to kill pathogens and survive, similar to cancer cells. The metabolic reprogramming in mitochondria is also associated with altered mitochondrial morphology. Mitochondrial dynamics can control T cell fate through metabolic programming. Mitochondrial fission will facilitate glycolysis and mitophagy which eliminate impaired fragmented mitochondria via fission (Fig. 1).
Mitophagy is an important method to remove damaged mitochondria by isolating dysfunctional mitochondria from healthy ones by double-membrane vesicles called autophagosomes and subsequently delivering autophagosomes to lysosomes. It protects body cells against septic stress, which can be strongly activated by mitochondrial depolarization before damage triggers necrosis. The canonical signal pathways are PINK1/Parkin and DJ-1 pathway. ROS induced mitochondrial damage might be a necessary activator to mitophagy. In the pathway, PINK1 kinase accumulates on the mitochondria and phosphorylates mitofusin 2 (MFN2). Parkin E3 ligase binds phosphorylated MFN2 and localizes to the mitochondria. The ubiquitination of several proteins on mitochondrial surface and various adapter proteins, including MFN1, MFN2, optic atrophy protein 1 (OPA1), and VDAC, are associated with the mitophagy, ultimately facilitating the elimination of the mitochondrial content. Moreover, VDAC was shown to be necessary for the PINK1/Parkin-directed mitophagy of damaged mitochondria. LPS injection significantly downregulated MFN1, MFN2, and OPA1, which are primary regulators of mitochondrial fusion. However, excessive mitochondrial fission and mitophagy can compromise the metabolic capacity of a cell. During sepsis, mitochondrial dysfunction is characterized with calcium dysregulation, overproduction of ROS, opening of mPTP, and a final loss in mitochondrial membrane potential, which induces cell death if progressive. But if mitophagy occurs in myocardial cells instead of the above processes, myocardial cells will avoid massive death, benefiting cell survival.
On the other hand, the opening of mPTP is pivotal to the fate of mitochondria and cells. And from the content mentioned above, it is not the first choice of survival cells. Therefore, the reason to keep its functional opening is of interest. Cytochrome C can be released after mPTP opening to induce apoptosis. The cardiolipin located in IMM is required for the dissociation of cytochrome C after its oxidation, as activated calpain 1 cleaves Bid, inducing cytochrome C release. Therefore, oxidation resistance is critical for cell survival. mGPx4, is a kind of GPx4 transported to mitochondria after synthesis in cell nucleus. It can suppress the peroxidation of cardiolipin in mitochondria and inhibit the dissociation of cytochrome C from IMM in apoptosis. Furthermore, mGPx4 catalyzes the decomposition of hydrogen peroxide or organic hydroperoxides using the reduced form of glutathione as an electron donor. Meanwhile, mGPx4 can inactivate Adenine nucleotide translocator (ANT), a component of mPTP, to inhibit the opening of mPTP and the opening of VDAC. If the expression of GPx4 is upregulated when a myocardial cell is exposed to sepsis, the pathway of cell death including apoptosis and necrosis is suppressed, and then, the mitophagy is chosen to begin. However, cardiac mGPx4 decreases after sepsis, and the activity of GPx4 falls to 70% after 12–24 h. As mGPx4 is reductive and protective, the more reasonable explanation for the “contradiction” is that the expression of mGPx4 is not always increasing, and also has its compensational scope. Further research on the GPx4 expressed in a myocardial cell is required, especially focusing on the correlation between mitophagy and expression of GPx4 (Fig. 1).
Sepsis is a result of uncontrolled primary and secondary infection under the condition of abnormal immunity. It will further result in tissue damage, cellular compromise, and molecular dysregulation, further initiating organ dysfunction and multiorgan failure. In SIMD survivors, necrosis of myocardial cells is little, which indicates the damage from host immune cells and pathogens is not intensive enough to induce necrosis, compared with not massive apoptosis. Therefore, there would be a balance between host immunity and pathogens during SIMD as immune cells can still not clear the pathogens. Immunosuppression involving innate immune and adaptive immunity has always been seen in sepsis because of lymphocyte apoptosis via caspases 8/9 and finally caspase 3 by both mitochondrial-mediated and receptor-mediated pathways. A decreased production of inflammatory cytokines has also been demonstrated such as decreased TNF, IL-1α, IL-6, and IL-12, interferon γ (IFN γ), and macrophage colony-stimulating factor (GM-CSF). Protein expressed on the lymphocyte also change. And these changes include the downregulation of CD127 and Bcl-2, and the upregulation of inhibitory receptors. Sepsis can also induce a subset of neutrophils with suppressive properties, as these neutrophils produce large amounts of the immunosuppressive cytokine IL-10 during sepsis. The most dominant function of macrophages is the phagocytosis of both pathogens and apoptotic cells. Macrophages’ clearance of innate immune cells can also be weakened by an increasing production of IL-10 from neutrophils and pyroptosis, a type of programmed cell death, via caspases 11 after detecting the LPS invasion in cytosol. Pyroptosic cell can be finally uptake by the neutrophil in response to phagocytosis, which might be able to resist pyroptosis in response to some inflammasome activators. During sepsis, neutrophil apoptosis is delayed in contrast to the lymphocytes undergoing accelerated apoptosis, which indicates that (1) neutrophils may last longer in sepsis than lymphocytes, (2) the clearance function of lymphocytes is actually impaired, and (3) increasing pyroptosis exists. In addition, Gpx4 expressed by cells from the myeloid lineage plays a major role in attenuating lipid peroxidation, inflammasome activation, and pyroptotic cell death in the context of sepsis. The depletion of Gpx4 results in increased septic lethality. GPx4 may be a requisite gateway to pyroptosis at least via caspases 11. Therefore, pyroptosis will take more account of the programmed cell death of innate immune cells. In this way, a balance can be achieved. Although immune cells are suppressed, pathogens can still be swallowed in their cytoplasm which can further decrease the damage from both immunity and pathogens. This “balanced” status of survivors can be ended with the improvement of host immunity. And continuous increase of pyroptosis means the host immunity is still in suppressed and pathogens’ virulence is not attenuated, indicating poor outcomes. It was also demonstrated that increased LPS-induced pyroptosis and the inhibition of autophagy by highly expressed ZFAS1 could aggravate the progression of SIMD in the in vivo and in vitro model (Fig. 2).
Some basic research related to the enhancement of immunity has been carried out such as C5a inhibitor used to treat sepsis in mice, Fms-like tyrosine kinase 3 ligand (Flt3L) used to stimulate the expansion and differentiation of NK cells and dendritic cells (DC) in infectious mice, and IFN γ used to restore energy metabolism in tolerant monocytes of mice. And in clinical, the administration of GM-CSF therapy was showed to facilitate the reversal of immunoparalysis in patients with multiple organ dysfunction syndrome (MODS). As SIMD is characteristic with insufficient function without obvious necrosis of myocardial cells, it will improve after sepsis is over. Therefore, enhancing body immunity as mentioned examples including enhancing the function of associated cytokines, complement, immune cells and their energy metabolism will contribute to SIMD directly and indirectly. As further explanation, for the heart function under the condition of immunosuppression, clearing necrotic or apoptotic myocardial cells will also further weaken the function of the innate immune cells, which is not beneficial for the recovery. The function of immune cells will be impaired and further apoptosis will be induced by the swallowed pathogen which cannot be cleared, if the mitochondria are reduced to an extent via mitophagy. Therefore, enhancing the function of immunity and treating the primary infection can decrease the apoptosis of immune cells and the proportion of pyroptosis. It can further improve the clearance of pathogens by host immune cells and weaken the suppressing signal from the inflammatory environment, further recovering myocardial cells after the fading of related stimulus of sepsis.
In SIMD, metabolism reprogramming would occur in both immune cells and myocardial cells. Under the homeostatic condition, immune cells rely on oxidative phosphorylation as the energy sources of ATP production. It will be shifted to aerobic glycolysis during sepsis, which is known as Warburg effect. It was suggested that the glycolysis of macrophage facilitated a macrophage proinflammatory phenotype and induced IL-1β production. Moreover, aerobic glycolysis could provide ATP for the immune response immediately. Aerobic glycolysis exists during critical illness in both immune cells and the other cells. And if fission, mitophagy, and aerobic glycolysis occur in myocardial cells, it will reduce the damage from mtROS and keep myocardial cells from massive apoptosis, which provide myocardial cells more opportunities to recover after sepsis. However, the inhibition of aerobic glycolysis by 2-DG significantly improves the survival outcome in bacterial sepsis. It is because lactate significantly increases after the shift of the energy metabolism to glycolysis during sepsis. And the immunosuppressive effects of the tumor-derived lactate have been shown on a variety of cell types in the surrounding microenvironment, and lactate has been suggested to induce M2-like macrophage polarization through an HIF-1a-dependent mechanism. According to the content mentioned above, if the inhibition of aerobic glycolysis is applied during immunosuppression, it has the similar role with the enhancement of body immunity, as it can alleviate the immunosuppressive effects of lactate by decreasing its production.
Another question is whether SIMD is mainly caused by inflammatory environment because of both slightly reversible damage and the epigenetic regulation of gene expression. It has been demonstrated that sirtuin 1 and sirtuin 6 can epigenetically shift substrate selection in septic mouse or human monocytes from the glucose fueling of the immune resistance to the fatty acid fueling of immune tolerance, and mitochondrial sirtuin 3 expression could be increased by sirtuin 1 to support mitochondrial catabolic energetics and activate the antioxidant pathways. Physiologically, oxidative phosphorylation is the first choice, as ATP is the basis for cells. Even under the depression of various signal pathways mainly and primarily caused by PAMPs and DAMPs, the epigenetic regulating gene expression can have a more positive effect on a healthy cell than on a suppressed cell in sepsis, which can try to generate more ATP. In contrast, the signal of mitophagy may be the dominant regulating signal in a suppressed cell, which may also process the apoptosis or necrosis when the damage is caused by severe inflammation (Fig. 1).
Conclusions
Conclusions
SIMD, as a common complication in septic patients, is associated with increased mortality. Changes in any part of CICR and excitation–contraction coupling (ECC) influence the heart function upon exposure to inflammatory environment and damage from inflammatory mediators and cytokines after the initiation of an immune reaction on pathogens. Mitophagy may be the compressive choice of a myocardial cell when facing sepsis, and is even chosen in case of death through necrosis or apoptosis or swallowing by macrophages and degeneration. Sepsis is a result of uncontrolled primary and secondary infections under the condition of abnormal immunity. Immunosuppression has always been observed in the case of sepsis, featured by a significant apoptosis of immune cells and a comparative increase in regulatory T cell and IL-10. Enhancing the body’s immunity may be more efficient to prevent or improve SIMD and control sepsis, besides the treatment of the primary infection. However, the research on the correlation between mitophagy and expression of GPx4, the recognition of the transitional or cut-off point of SIMD and immunosuppression to achieve early prevention, and the selection of the biomarkers that can be used to indicate the possibility of SIMD and immunosuppression need further research.
END
Translation
Wang Wenjun, MD
Resident Physician at Shandong First Medical University Affiliated Provincial Hospital
Online Express
Translation:Wang Wenjun
Editor: Song Xuan
Reviewed by: Wang Chunting
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Note:
Wang Wenjun: Shandong First Medical University Affiliated Provincial Hospital
Wang Chunting: Shandong First Medical University Affiliated Provincial Hospital
Song Xuan: Shandong First Medical University
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