Mitochondrial function in immune cells in health and disease

One of the main functions of mitochondria is production of ATP for cellular energy needs, however, it becomes more recognized that mitochondria are involved in differentiation and activation processes of immune cells. Upon activation, immune cells have a high need for energy. Immune cells have different strategies to generate this energy. In pro-inflammatory cells, such as activated monocytes and activated T and B cells, the energy is generated by increasing glycolysis, while in regulatory cells, such as regulatory T cells or M2 macrophages, energy is generated by increasing mitochondrial function and beta-oxidation.Except for being important for energy supply during activation, mitochondria also induce immune responses. During an infection, they release mitochondrial danger associated molecules (DAMPs) that resemble structures of bacterial derived pathogen associated molecular patterns (PAMPs). Such mitochondrial DAMPS are for instance mitochondrial DNA with hypomethylated CpG motifs or a specific lipid that is only present in prokaryotic bacteria and mitochondria, i.e. cardiolipin. Via release of such DAMPs, mitochondria guide the immune response towards an inflammatory response against pathogens. This is an important mechanism in early detection of an infection and in stimulating and sustaining immune responses to fight infections. However, mitochondrial DAMPs may also have a negative impact. If mitochondrial DAMPs are released by damaged cells, without the presence of an infection, such as after a trauma, mitochondrial DAMPs may induce an undesired inflammatory response, resulting in tissue damage and organ dysfunction. Thus, immune cells have developed mechanisms to prevent such undesired immune activation by mitochondrial components.In the present narrative review, we will describe the current view of mitochondria in regulation of immune responses. We will also discuss the current knowledge on disturbed mitochondrial function in immune cells in various immunological diseases.     

Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia

In this study, heart and diaphragm mitochondria produced 0.69 and 0.77 nmol nitric oxide (NO)/min mg protein, rates that account for 67 and 24% of maximal cellular NO production, respectively. Endotoxemia and septic shock occur with an exacerbated inflammatory response that damages tissue mitochondria. Skeletal muscle seems to be one of the main target organs in septic shock, showing an increased NO production and early oxidative stress. The kinetic properties of mitochondrial nitric oxide synthase (mtNOS) of heart and diaphragm were determined. For diaphragm, the KM values for O2 and L-Arg were 4.6 and 37 microM and for heart were 3.3 and 36 microM. The optimal pH for mtNOS activity was 6.5 for diaphragm and 7.0 for heart. A marked increase in mtNOS activity was observed in endotoxemic rats, 90% in diaphragm and 30% in heart. Diaphragm and heart mitochondrial O2*- and H2O2 production were 2- to 3-fold increased during endotoxemia and Mn-SOD activity showed a 2-fold increase in treated animals, whereas catalase activity was unchanged. One of the current hypotheses for the molecular mechanisms underlying the complex condition of septic shock is that the enhanced NO production by mtNOS leads to excessive peroxynitrite production and protein nitration in the mitochondrial matrix, causing mitochondrial dysfunction and contractile failure.     

High‐fat diet affects skeletal muscle mitochondria comparable to pressure overload‐induced heart failure

In heart failure, high‐fat diet (HFD) may exert beneficial effects on cardiac mitochondria and contractility. Skeletal muscle mitochondrial dysfunction in heart failure is associated with myopathy. However, it is not clear if HFD affects skeletal muscle mitochondria in heart failure as well. To induce heart failure, we used pressure overload (PO) in rats fed normal chow or HFD. Interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) from gastrocnemius were isolated and functionally characterized. With PO heart failure, maximal respiratory capacity was impaired in IFM but increased in SSM of gastrocnemius. Unexpectedly, HFD affected mitochondria comparably to PO. In combination, PO and HFD showed additive effects on mitochondrial subpopulations which were reflected by isolated complex activities. While PO impaired diastolic as well as systolic cardiac function and increased glucose tolerance, HFD did not affect cardiac function but decreased glucose tolerance. We conclude that HFD and PO heart failure have comparable effects leading to more severe impairment of IFM. Glucose tolerance seems not causally related to skeletal muscle mitochondrial dysfunction. The additive effects of HFD and PO may suggest accelerated skeletal muscle mitochondrial dysfunction when heart failure is accompanied with a diet containing high fat.     

Diaphragm and cardiac mitochondrial creatine kinases are impaired in sepsis.

Previous studies indicate that ATP formation by the electron transport chain is impaired in sepsis. However, it is not known whether sepsis affects the mitochondrial ATP transport system. We hypothesized that sepsis inactivates the mitochondrial creatine kinase (MtCK)-high energy phosphate transport system. To examine this issue, we assessed the effects of endotoxin administration on mitochondrial membrane-bound creatine kinase, an important trans-mitochondrial ATP transport system. Diaphragms and hearts were isolated from control (n = 12) and endotoxin-treated (8 mg.kg(-1).day(-1); n = 13) rats after pentobarbital anesthesia. We isolated mitochondria using techniques that allow evaluation of the functional coupling of mitochondrial creatine kinase MtCK activity to oxidative phosphorylation. MtCK functional activity was established by 1) determining ATP/creatine-stimulated oxygen consumption and 2) assessing total creatine kinase activity in mitochondria using an enzyme-linked assay. We examined MtCK protein content using Western blots. Endotoxin markedly reduced diaphragm and cardiac MtCK activity, as determined both by ATP/creatine-stimulated oxygen consumption and by the enzyme-linked assay (e.g., ATP/creatine-stimulated mitochondrial respiration was 173.8 +/- 7.3, 60.5 +/- 9.3, 210.7 +/- 18.9, was 67.9 +/- 7.3 natoms O.min(-1).mg(-1) in diaphragm control, diaphragm septic, cardiac control, and cardiac septic samples, respectively; P < 0.001 for each tissue comparison). Endotoxin also reduced diaphragm and cardiac MtCK protein levels (e.g., protein levels declined by 39.5% in diaphragm mitochondria and by 44.2% in cardiac mitochondria; P < 0.001 and P = 0.009, respectively, comparing sepsis to control conditions). Our data indicate that endotoxin markedly impairs the MtCK-ATP transporter system; this phenomenon may have significant effects on diaphragm and cardiac function.     

Mitochondrial dysfunction in sepsis: evidence from bacteraemic baboons and endotoxaemic rabbits

Mitochondria, that provide most of the ATP needed for cell work, and that play numerous specific functions in biosyntheses and degradations, as well as contributing to Ca²⁺; signaling, also play a key role in the pathway to cell death. Impairment of mitochondrial functions caused by mutations of mt-genome, and by acute processes, are responsible for numerous diseases.The involvement of impaired mitochondria in the pathogenesis of sepsis is discussed. By means of the skinned fiber technique and high resolution respirometry, we have detected significantly reduced rates of mitochondrial respiration in heart and skeletal muscle of endotoxaemic rabbits. Mitochondria from heart were more affected than those from skeletal muscle. Decreased respiration rates were accompanied by reduced activities of complex I+III of the respiratory chain. Endotoxin-caused impairment was also detectable at the level of the Langendorff perfused heart, where the coronary vascular resistance was significantly increased.For an investigation of the influence of bacteraemia on the mitochondrial respiratory chain, baboons were made septic by infusion of high and low amounts of E. coli. For complex I+III and II+III, a clear dose-dependent decrease was detectable and in animals which died in septic shock, a further decrease of enzyme activities in comparison to the controls were found.These results are discussed in the light of current knowledge on the role of mitochondria in cell pathology in respect to sepsis.In conclusion, we present evidence that mitochondrial function is disturbed during sepsis. Besides ischaemic and poison-induced disturbances of mitochondrial function, sepsis is a further example of an acute disease where impaired mitochondria have to be taken into account.     

The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by α-lipoic acid

The aims of this work were to study the mitochondrial function and to evaluate (a) the oxidative stress in real time in an acute model of endotoxemia and (b) the effect of α-lipoic acid (LA, 100 mg/kg) as a therapeutic strategy to be considered. In rats treated with lipopolisaccharide (LPS, 10 mg/kg), a 1.4-fold increase was observed in in situ skeletal muscle chemiluminescence. Experimental sepsis increased oxygen consumption in tissue cubes (1 mm³) by 30% for heart and diaphragm and impaired state 3 mitochondrial respiration rate in the three organs (liver, diaphragm and heart) studied. Only complex I activity in heart and diaphragm and complex IV activity in diaphragm were found impaired in this septic model. The production of NO by submitochondrial membranes was found increased by 80% in the diaphragm and by 35% in the heart of septic rats. The treatment with LA prevented the oxidative stress and mitochondrial dysfunction observed in this model.     

Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice

The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative/oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS(+/+)) and inducible nitric oxide synthase-deficient (iNOS(-/-)) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS(+/+) mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS(-/-) mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS(-/-) mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis.     

Sepsis-Induced Cardiac Mitochondrial Dysfunction Involves Altered Mitochondrial-Localization of Tyrosine Kinase Src and Tyrosine Phosphatase SHP2

Our previous research demonstrated that sepsis produces mitochondrial dysfunction with increased mitochondrial oxidative stress in the heart. The present study investigated the role of mitochondria-localized signaling molecules, tyrosine kinase Src and tyrosine phosphatase SHP2, in sepsis-induced cardiac mitochondrial dysfunction using a rat pneumonia-related sepsis model. SD rats were given an intratracheal injection of Streptococcus pneumoniae, 4×10(6) CFU per rat, (or vehicle for shams); heart tissues were then harvested and subcellular fractions were prepared. By Western blot, we detected a gradual and significant decrease in Src and an increase in SHP2 in cardiac mitochondria within 24 hours post-inoculation. Furthermore, at 24 hours post-inoculation, sepsis caused a near 70% reduction in tyrosine phosphorylation of all cardiac mitochondrial proteins. Decreased tyrosine phosphorylation of certain mitochondrial structural proteins (porin, cyclophilin D and cytochrome C) and functional proteins (complex II subunit 30kD and complex I subunit NDUFB8) were evident in the hearts of septic rats. In vitro, pre-treatment of mitochondrial fractions with recombinant active Src kinase elevated OXPHOS complex I and II-III activity, whereas the effect of SHP2 phosphatase was opposite. Neither Src nor SHP2 affected complex IV and V activity under the same conditions. By immunoprecipitation, we showed that Src and SHP2 consistently interacted with complex I and III in the heart, suggesting that complex I and III contain putative substrates of Src and SHP2. In addition, in vitro treatment of mitochondrial fractions with active Src suppressed sepsis-associated mtROS production and protected aconitase activity, an indirect marker of mitochondrial oxidative stress. On the contrary, active SHP2 phosphatase overproduced mtROS and deactivated aconitase under the same in vitro conditions. In conclusion, our data suggest that changes in mitochondria-localized signaling molecules Src and SHP2 constitute a potential signaling pathway to affect mitochondrial dysfunction in the heart during sepsis.     

TNF-alpha-induced mitochondrial oxidative stress and cardiac dysfunction: restoration by superoxide dismutase mimetic Tempol

Mitochondria are indispensable for bioenergetics and for the regulation of physiological/signaling events in cellular life. Although TNF-alpha-induced oxidative stress and mitochondrial dysfunction are evident in several pathophysiological states, the molecular mechanisms coupled with impaired cardiac function and its potential reversal by drugs such as Tempol or apocyanin have not yet been explored. Here, we hypothesize that TNF-alpha-induced oxidative stress compromises cardiac function by altering the mitochondrial redox state and the membrane permeability transition pore (MPTP) opening, thereby causing mitochondrial dysfunction. We measured the redox states in the cytosol and mitochondria of the heart to understand the mechanisms related to the MPTP and the antioxidant defense system. Our studies demonstrate that TNF-alpha-induced oxidative stress alters redox homeostasis by impairing the MPTP proteins adenine nucleotide translocator and voltage-dependent anion channel, thereby resulting in the pore opening, causing uncontrolled transport of substances to alter mitochondrial pH, and subsequently leading to dysfunction of mitochondria and attenuated cardiac function. Interestingly, we show that the supplementation of Tempol along with TNF-alpha restores mitochondrial and cardiac function.     

Alterations in mitochondrial dynamics with age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24–26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4–6 months) mice hearts impair cardiomyocyte contractility and shows aging‐like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age‐related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.     

心衰进程中非编码RNA对线粒体功能的调控作用

心衰长久以来一直缺少有效治疗方法,给社会造成了巨大的经济和民生负担,新诊断标志物的确认和治疗方法的研发十分迫切。线粒体功能障碍与心衰发生和发展密切相关,以线粒体为基础的能量供应紊乱、钙失衡、氧化应激和细胞死亡在心衰的发展中起着重要作用,但线粒体调控的具体机制还不十分清楚。非编码RNA被证实在表观调控、转录后修饰、翻译调节等多方面发挥重要调控作用。研究表明,包括miRNA、lncRNA、circRNA在内的大量非编码RNA在心脏发育和心脏疾病发展过程中存在差异表达,并在线粒体蛋白稳态、氧化磷酸化、氧化应激、凋亡与自噬等调控中发挥了重要作用,进而影响心衰等心脏疾病的发生发展,但其详细机制尚未完全阐明。本文就近年心衰发生和发展过程中非编码RNA调控线粒体功能机制的相关研究进行综述,梳理了近年来非编码RNA在调节线粒体结构与功能进而影响心衰发展方面的研究进展,以期为心衰研究与治疗提供新的思路和靶点。     

Proteomic analysis of mitochondria reveals a metabolic switch from fatty acid oxidation to glycolysis in the failing heart

This work characterizes the mitochondrial proteomic profile in the failing heart and elucidates the molecular basis of mitochondria in heart failure. Heart failure was induced in rats by myocardial infarction, and mitochondria were isolated from hearts by differential centrifugation. Using two-dimen- sional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry, a system biology approach was employed to investigate differences in mitochondrial proteins between normal and failing hearts. Mass spectrometry identified 27 proteins differentially expressed that involved in energy metabolism. Among those, the up-regulated proteins included tricarboxylic acid cycle enzymes and pyruvate dehydrogenase complex subunits while the down-regulated proteins were involved in fatty acid oxidation and the OXPHOS complex. These results suggest a substantial metabolic switch from free fatty acid oxidation to glycolysis in heart failure and provide molecular evidence for alterations in the structural and functional parameters of mitochondria that may contribute to cardiac dysfunction during ischemic injury.     

Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction

Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as when cellular energy needs and energy production from mitochondria fatty acid β-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific perilipin 5 (Plin5) overexpression (MHC-Plin5), a member of the perilipin protein family. Hearts from MHC-Plin5 mice expressed at least 4-fold higher levels of plin5 and exhibited a 3.5-fold increase in triglyceride content versus nontransgenic littermates. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of peroxisome proliferator-activated receptor (PPAR)α target genes, decreased mitochondria function, and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative-induced genes via NF-E2-related factor 2 antioxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and it promotes cardiac steatosis without major heart function impairment.     

Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases

As a nicotinamide adenine dinucleotide (NAD)⁺-dependent protein deacetylase, SIRT3 is highly expressed in tissues with high metabolic turnover and mitochondrial content. It has been demonstrated that SIRT3 plays a critical role in maintaining normal mitochondrial biological function through reversible protein lysine deacetylation. SIRT3 has a variety of substrates that are involved in mitochondrial biological processes such as energy metabolism, reactive oxygen species production and clearance, electron transport chain flux, mitochondrial membrane potential maintenance, and mitochondrial dynamics. In the suppression of SIRT3, functional deficiencies of mitochondria contribute to the development of various cardiovascular disorders. Activation of SIRT3 may represent a promising therapeutic strategy for the improvement of mitochondrial function and the treatment of relevant cardiovascular disorders. In the current review, we discuss the emerging roles of SIRT3 in mitochondrial derangements and subsequent cardiovascular malfunctions, including cardiac hypertrophy and heart failure, ischemia-reperfusion injury, and endothelial dysfunction in hypertension and atherosclerosis.     

New aspects of impaired mitochondrial function in heart failure

This minireview focuses on the impairment of function in cardiac mitochondria in heart failure (HF). It is generally accepted that chronic energy starvation leads to cardiac mechanical dysfunction in HF. Mitochondria are the primary ATP generator for the heart. Current evidence suggests that the assembly of the electron transport chain (ETC) into respirasomes provides structural support for mitochondrial oxidative phosphorylation by facilitating electron channeling and perhaps by preventing electron leak and superoxide production. Defects have been purported to occur in the individual ETC complexes or components of the phosphorylation apparatus in HF, but these defects have not been linked to impaired mitochondrial function. Moreover, studies that reported decreased mitochondrial oxidative phosphorylation in HF did not identify the site of the defect. We propose a sequential mechanistic pathway in which the decrease in functional respirasomes in HF is the primary event causing decreased oxidative phosphorylation and increased reactive oxygen species production, leading to a progressive decrease in cardiac performance.     

Cardiac mitochondrial damage and loss of ROS defense after burn injury: the beneficial effects of antioxidant therapy.

Mechanisms of burn-related cardiac dysfunction may involve defects in mitochondria. This study determined 1) whether burn injury alters myocardial mitochondrial integrity and function; and 2) whether an antioxidant vitamin therapy prevented changes in cardiac mitochondrial function after burn. Sprague-Dawley rats were given a 3 degrees burn over 40% total body surface area and fluid resuscitated. Antioxidant vitamins or vehicle were given to sham and burn rats. Mitochondrial and cytosolic fractions were prepared from heart tissues at several times postburn. In mitochondria, lipid peroxidation was measured to assess oxidative stress, mitochondrial outer membrane damage and cytochrome-c translocation were determined to estimate mitochondrial integrity, and activities of SOD and glutathione peroxidase were examined to evaluate mitochondrial antioxidant defense. Cardiac function was measured by Langendorff model in sham and burn rats given either vitamins or vehicle. Twenty-four hours postburn, mitochondrial outer membrane damage was progressively increased to approximately 50%, and cytosolic cytochrome-c gradually accumulated to approximately three times more than that measured in shams, indicating impaired mitochondrial integrity. Maximal decrease of mitochondrial SOD activity occurred 8 h postburn ( approximately 63.5% of shams), whereas maximal decrease in glutathione peroxidase activity persisted 2-24 h postburn ( approximately 60% of shams). In burn animals, lipid peroxidation in cardiac mitochondria increased 30-50%, suggesting burn-induced oxidative stress. Antioxidant vitamin therapy prevented burn-related loss of membrane integrity and antioxidant defense in myocardial mitochondria and prevented cardiac dysfunction. These data suggest that burn-mediated mitochondrial dysfunction and loss of reactive oxygen species defense may play a role in postburn cardiac dysfunction.     

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.     

The role of mitochondria in sepsis-induced cardiomyopathy

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction, often termed sepsis-induced cardiomyopathy, is a frequent complication and is associated with worse outcomes. Numerous mechanisms contribute to sepsis-induced cardiomyopathy and a growing body of evidence suggests that bioenergetic and metabolic derangements play a central role in its development; however, there are significant discrepancies in the literature, perhaps reflecting variability in the experimental models employed or in the host response to sepsis. The condition is characterised by lack of significant cell death, normal tissue oxygen levels and, in survivors, reversibility of organ dysfunction. The functional changes observed in cardiac tissue may represent an adaptive response to prolonged stress that limits cell death, improving the potential for recovery. In this review, we describe our current understanding of the pathophysiology underlying myocardial dysfunction in sepsis, with a focus on disrupted mitochondrial processes.     

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 μmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.