Mitochondrial dysfunction and the inflammatory response

López-Armada, M.J.; Riveiro-Naveira, Romina R.; Vaamonde‐García, Carlos; Valcarcel‐Ares, Marta Noa

doi:10.1016/j.mito.2013.01.003

Cited by 421 publications

(319 citation statements)

References 173 publications

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“…Mitochondrial superoxide regulation is fundamental to the maintenance of cell homeostasis. Lack of regulation can result in damage to mitochondrial DNA and mitochondrial proteins, leading to a feed-forward loop of increasing oxidative stress (2,8,45,46). When the mechanisms of mitochondrial ROS regulation are not in place or are overwhelmed, mitochondrial oxidative stress will have effects on cellular processes beyond the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…While mitochondria can promote inflammation via NF-B signaling and NLRP3 inflammasome formation, inflammation can lead to mitochondrial dysfunction, which can compound the severity of exaggerated inflammatory conditions such as sepsis (4)(5)(6)(7)(8)(9)(10). As the site of the electron transport chain within cells, mitochondria are a major source of reactive oxygen species (ROS) (mainly superoxide anions).…”

mentioning

confidence: 99%

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Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

et al. 2015

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T he roles that mitochondria play in antiviral signaling, via mitochondrial antiviral-signaling protein and promotion of inflammation and apoptosis, are well established (1-3); however, their importance in innate immunity is only now becoming clear. While mitochondria can promote inflammation via NF-B signaling and NLRP3 inflammasome formation, inflammation can lead to mitochondrial dysfunction, which can compound the severity of exaggerated inflammatory conditions such as sepsis (4-10). As the site of the electron transport chain within cells, mitochondria are a major source of reactive oxygen species (ROS) (mainly superoxide anions). ROS play diverse roles in cellular and organismal health, especially in innate immunity and inflammation. While the use of ROS to clear infections is beneficial to the host, inappropriate ROS production or lack of ROS neutralization can damage host DNA, proteins, and cell membranes. ROS-induced cellular damage can contribute to the undesired side effects of infectious and inflammatory diseases. Mechanisms are in place in hosts, and even some pathogens, to chemically convert ROS into less toxic compounds; however, overproduction of ROS can overwhelm host antioxidants. Thus, a better understanding of the impact of mitochondria, ROS, and mechanisms for neutralization of ROS on innate immunity could lead to improved treatments for infectious diseases and inflammatory disorders.The cellular mechanisms to neutralize ROS include the glutathione system, catalases, and the superoxide dismutase (SOD) family of enzymes. As superoxide producers, mitochondria are equipped with nuclear-encoded, mitochondrially localized SODs (SOD2, MnSOD) that convert superoxide into hydrogen peroxide. The deleterious effects of mitochondrial superoxide are demonstrated by mutations in SOD2 being implicated in idiopathic cardiomyopathy, age-related macular degeneration, aberrant brain morphology, motor neuron disease, vascular complications of diabetes, and cancer, whereas overexpression of SOD2 increases the Drosophila life span (11,(69)(70)(71)(72). Despite the importance of SOD2 and the regulation of ROS for health, surprisingly little is known about the role of SOD2 in immunity. Numerous studies have implicated SOD2 in the immune response, but few have defined functional roles for SOD2 in immunity. SOD2 is upregulated in response to lipopolysaccharide (LPS), poly(I·C), beta-glucan, and numerous pathogens in multiple cell types and organisms (12-17). Functionally, SOD2 was found to be necessary for the phorbol myristate acetate-induced respiratory burst response and cell survival upon poly(I·C) exposure in vitro (16,17). In a mouse model with SOD2 deleted specifically from thymocytes, the animals did not mount an effective adaptive immune response to influenza virus infection because of disrupted T-cell

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

et al. 2015

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“…3 Furthermore, mitochondria dysfunction is frequently associated with pathological conditions, including cancer and inflammatory disorders. 4,5 The mechanisms that control mitochondrial activity and dynamics are, however, not fully understood.…”

Section: Introductionmentioning

confidence: 99%

miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

Duroux-Richard

Roubert

Ammari

et al. 2016

Blood

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Key Points• miR-125b reduces mitochondrial respiration and promotes elongation of mitochondrial network through BIK and MTP18 silencing, respectively. • The miR-125b/BIK/MTP18 axis promotes adaptation of monocytes to inflammation.Metabolic changes drive monocyte differentiation and fate. Although abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders, molecular events regulating mitochondrial activity to control life and death in monocytes remain poorly understood. We show here that, in human monocytes, microRNA-125b (miR-125b) attenuates the mitochondrial respiration through the silencing of the BH3-only proapoptotic protein BIK and promotes the elongation of the mitochondrial network through the targeting of the mitochondrial fission process 1 protein MTP18, leading to apoptosis. Proinflammatory activation of monocyte-derived macrophages is associated with a concomitant increase in miR-125b expression and decrease in BIK and MTP18 expression, which lead to reduced oxidative phosphorylation and enhanced mitochondrial fusion. In a chronic inflammatory systemic disorder, CD14 1 blood monocytes display reduced miR-125b expression as compared with healthy controls, inversely correlated with BIK and MTP18 messenger RNA expression. Our findings not only identify BIK and MTP18 as novel targets for miR-125b that control mitochondrial metabolism and dynamics, respectively, but also reveal a novel function for miR-125b in regulating metabolic adaptation of monocytes to inflammation. Together, these data unravel new molecular mechanisms for a proapoptotic role of miR-125b in monocytes and identify potential targets for interfering with excessive inflammatory activation of monocytes in inflammatory disorders. (Blood. 2016;128(26): 3125-3136)

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“…TNF-α generates ROS at the mitochondrial inner membrane, which may easily result in the progressive destruction of the mtDNA, possibly because of its proximity to the site of ROS production TNFα also decreased complex III activity of mitochondria which might be because of its higher susceptibility to ROS-induced damage or due to decrease of the mtDNA copy number leads to a decrease in complex III activity decrease [33,71,73,74]. Moreover the activity of complex I, ATP production, and mitochondrial membrane potential (Δψm) has shown to be affected due to TNF-α [75]. Therefore, complex I together with complex III have been suggested to be major sources of ROS.…”

Section: Tumor Necrosis Factor α (Tnf-α)mentioning

confidence: 99%

Mechanism of Mitochondrial Dysfunction during Chronic Fatigue

Muluye¹,

Bian²

2017

Int J Phys Med Rehabil

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A clinically defined condition characterized by persistent, severe, disabling fatigue lasting more than six months that is not reversed by sleep is regarded as chronic fatigue (CF). Fatigue is a complex phenomenon determined by several factors, including psychological health but at the biochemical level fatigue is related to the metabolic energy available to tissues and cells, mainly through mitochondrial respiration. Fatigue is the most common symptom of poorly functioning mitochondria. therefore dysfunction of these organelles may be the cause of the fatigue seen in CF. There is a great progress in the molecular understanding of mitochondrial disorder but the relation of mitochondrial dysfunction with CF and the underlying mechanism is not identified well in addition treatment of fatigue is still inadequate. In this review we try to summarize the relation between CF with mitochondrial dysfunction and determine the underline mechanism.

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Mitochondrial dysfunction and the inflammatory response

Cited by 421 publications

References 173 publications

Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

Mechanism of Mitochondrial Dysfunction during Chronic Fatigue

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