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1.
Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.
Geisberger, S, Bartolomaeus, H, Neubert, P, Willebrand, R, Zasada, C, Bartolomaeus, T, McParland, V, Swinnen, D, Geuzens, A, Maifeld, A, et al
Circulation. 2021;(2):144-158
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Abstract
BACKGROUND Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. METHODS Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichiacoli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.
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TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration.
Russ, K, Teku, G, Bousset, L, Redeker, V, Piel, S, Savchenko, E, Pomeshchik, Y, Savistchenko, J, Stummann, TC, Azevedo, C, et al
Cell reports. 2021;(12):108895
Abstract
Here, we examine the cellular changes triggered by tumor necrosis factor alpha (TNF-α) and different alpha-synuclein (αSYN) species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNF-α display a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the nuclear factor κB (NF-κB) pathway, and release of pro-inflammatory cytokines, whereas those treated with high-molecular-weight αSYN fibrils acquire a reactive antigen (cross)-presenting phenotype with upregulation of major histocompatibility complex (MHC) genes and increased human leukocyte antigen (HLA) molecules at the cell surface. Surprisingly, the cell surface location of MHC proteins is abrogated by larger F110 fibrillar polymorphs, despite the upregulation of MHC genes. Interestingly, TNF-α and αSYN fibrils compete to drive the astrocyte immune reactive response. The astrocyte immune responses are accompanied by an impaired mitochondrial respiration, which is exacerbated in Parkinson's disease (PD) astrocytes. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.
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Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.
Simon, MS, Schiweck, C, Arteaga-Henríquez, G, Poletti, S, Haarman, BCM, Dik, WA, Schwarz, M, Vrieze, E, Mikova, O, Joergens, S, et al
Progress in neuro-psychopharmacology & biological psychiatry. 2021;:110391
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Abstract
BACKGROUND The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.
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Mitochondria-targeted compounds in the treatment of cancer.
Kafkova, A, Trnka, J
Neoplasma. 2020;(3):450-460
Abstract
Mitochondria are highly dynamic organelles involved in many cellular functions. Beyond their central role in metabolism, they also take a part in maintaining calcium homeostasis, cell death, immunity, and ROS production. Changes in these functions have been shown to be crucial for the adaptation and survival of cancer cells. Mitochondria, therefore, constitute a promising target for the development of novel anticancer agents. The triphenylphosphonium (TPP+) moiety has been widely used to target molecules into mitochondria. TPP+ derivatives of a variety of conventional cytostatic drugs, natural substances, metformin, antioxidants or a range of newly synthesized molecules have shown promising results against cancer cells. In this review, we discuss biochemical differences between cancer cells and normal cells with a specific focus on mitochondria, and how mitochondrially targeted molecules can be used to selectively affect mitochondrial function in normal and cancer cells. We summarize the published data on mitochondrially targeted anticancer agents and propose future research avenues.
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Redox Signaling from Mitochondria: Signal Propagation and Its Targets.
Ježek, P, Holendová, B, Plecitá-Hlavatá, L
Biomolecules. 2020;(1)
Abstract
Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.
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Inflammation and Mitochondrial Dysfunction in Autism Spectrum Disorder.
Gevezova, M, Sarafian, V, Anderson, G, Maes, M
CNS & neurological disorders drug targets. 2020;(5):320-333
Abstract
Autism Spectrum Disorders (ASD) is a severe childhood psychiatric condition with an array of cognitive, language and social impairments that can significantly impact family life. ASD is classically characterized by reduced communication skills and social interactions, with limitations imposed by repetitive patterns of behavior, interests, and activities. The pathophysiology of ASD is thought to arise from complex interactions between environmental and genetic factors within the context of individual development. A growing body of research has raised the possibility of identifying the aetiological causes of the disorder. This review highlights the roles of immune-inflammatory pathways, nitro-oxidative stress and mitochondrial dysfunctions in ASD pathogenesis and symptom severity. The role of NK-cells, T helper, T regulatory and B-cells, coupled with increased inflammatory cytokines, lowered levels of immune-regulatory cytokines, and increased autoantibodies and microglial activation is elucidated. It is proposed that alterations in mitochondrial activity and nitrooxidative stress are intimately associated with activated immune-inflammatory pathways. Future research should determine as to whether the mitochondria, immune-inflammatory activity and nitrooxidative stress changes in ASD affect the development of amygdala-frontal cortex interactions. A number of treatment implications may arise, including prevention-orientated prenatal interventions, treatment of pregnant women with vitamin D, and sodium butyrate. Treatments of ASD children and adults with probiotics, sodium butyrate and butyrate-inducing diets, antipurinergic therapy with suramin, melatonin, oxytocin and taurine are also discussed.
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Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Suboptimal Mitochondrial Function: Assessment, Treatment and Classification Implications.
Anderson, G, Maes, M
Current topics in medicinal chemistry. 2020;(7):524-539
Abstract
The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.
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Hypertension linked to allostatic load: from psychosocial stress to inflammation and mitochondrial dysfunction.
Mocayar Marón, FJ, Ferder, L, Saraví, FD, Manucha, W
Stress (Amsterdam, Netherlands). 2019;(2):169-181
Abstract
Although a large number of available treatments and strategies, the prevalence of cardiovascular diseases continues to grow worldwide. Emerging evidence supports the notion of counteracting stress as a critical component of a comprehensive therapeutic strategy for cardiovascular disease. Indeed, an unhealthy lifestyle is a burden to biological variables such as plasma glucose, lipid profile, and blood pressure control. Recent findings identify allostatic load as a new paradigm for an integrated understanding of the importance of psychosocial stress and its impact on the development and maintenance of cardiovascular disease. Allostasis complement homeostasis and integrates behavioral and physiological mechanisms by which genes, early experiences, environment, lifestyle, diet, sleep, and physical exercise can modulate and adapt biological responses at the cellular level. For example, variability is a physiological characteristic of blood pressure necessary for survival and the allostatic load in hypertension can contribute to its related cardiovascular morbidity and mortality. Therefore, the current review will focus on the mechanisms that link hypertension to allostatic load, which includes psychosocial stress, inflammation, and mitochondrial dysfunction. We will describe and discuss new insights on neuroendocrine-immune effects linked to allostatic load and its impact on the cellular and molecular responses; the links between allostatic load, inflammation, and endothelial dysfunction; the epidemiological evidence supporting the pathophysiological origins of hypertension; and the biological embedding of allostatic load and hypertension with an emphasis on mitochondrial dysfunction.
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Endometriosis Pathoetiology and Pathophysiology: Roles of Vitamin A, Estrogen, Immunity, Adipocytes, Gut Microbiome and Melatonergic Pathway on Mitochondria Regulation.
Anderson, G
Biomolecular concepts. 2019;(1):133-149
Abstract
Endometriosis is a common, often painful, condition that has significant implications for a woman's fertility. Classically, endometriosis has been conceptualized as a local estrogen-mediated uterine condition driven by retrograde menstruation. However, recent work suggests that endometriosis may be a systemic condition modulated, if not driven, by prenatal processes. Although a diverse array of factors have been associated with endometriosis pathophysiology, recent data indicate that the low body mass index and decreased adipogenesis may be indicative of an early developmental etiology with alterations in metabolic function crucial to endometriosis pathoetiology. The present article reviews the data on the pathoetiology and pathophysiology of endometriosis, suggesting key roles for alterations in mitochondria functioning across a number of cell types and body systems, including the immune system and gut microbiome. These changes are importantly regulated by decreases in vitamin A and its retinoic acid metabolites as well as increases in mitochondria estrogen receptor-beta and the N-acetylserotonin/melatonin ratio across development. This has treatment and future research implications for this still poorly managed condition, as well as for the association of endometriosis with a number of cancers.
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Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation.
Yarbro, JR, Pence, BD
Mechanisms of ageing and development. 2019;:111146
Abstract
Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that classical monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged classical monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged classical monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.