Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients

Krychtiuk, Konstantin A.; Ruhittel, Sarah; Hohensinner, Philipp J.; Koller, Lorenz; Kaun, Christoph; Lenz, Max; Bauer, Benedikt; Wutzlhofer, Lisa; Draxler, Dominik F.; Maurer, Gerald; Huber, Kurt; Wojta, Johann; Gisslinger, Heinz; Niessner, Alexander; Speidl, Walter S.

doi:10.1097/ccm.0000000000001311

Cited by 67 publications

(58 citation statements)

References 23 publications

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“…In addition to xenophagy, autophagy may also regulate immune responses and inflammation by controlling mitochondrial quality in sepsis. The levels of mtDNA are increased in plasma from patients with sepsis and associated with severity and mortality (81,82). In contrast, a recent study shows that copy number of mtDNA in monocytes and lymphocytes of patients with sepsis has been shown to decrease and inversely correlate with severity of illness (e.g., Acute Physiology and Chronic Health Evaluation II score, a commonly used scoring system for a mortality estimation) (83), suggesting that mtDNA can be released from these cells.…”

Section: Role Of Selective Autophagy In Sepsismentioning

confidence: 88%

Autophagy in Pulmonary Diseases

Nakahira

Porras

Choi

2016

Am J Respir Crit Care Med

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The pathogenesis of pulmonary diseases is often complex and characterized by multiple cellular events, including inflammation, cell death, and cell proliferation. The mechanisms by which these events are regulated in pulmonary diseases remain poorly understood. Autophagy is an essential process for cellular homeostasis and stress adaptation in eukaryotic cells. This highly conserved cellular process involves the sequestration of cytoplasmic components in double-membrane autophagosomes, which are delivered to lysosomes for degradation. The critical roles of autophagy have been demonstrated in a wide range of pathophysiological conditions. Emerging studies have identified that autophagy plays important roles in the pathogenesis of various lung diseases. In addition, autophagy has been shown to selectively degrade subcellular targets, including proteins, organelles, and pathogens. Here, we highlight the recent advances in the molecular regulation and function of autophagy in lung diseases.

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Section: Role Of Selective Autophagy In Sepsismentioning

confidence: 88%

Autophagy in Pulmonary Diseases

Nakahira

Porras

Choi

2016

Am J Respir Crit Care Med

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“…In this context, multiple lines of emerging evidence converge on the idea that mitochondria orchestrate responses to injurious and inflammatory stimuli by releasing a family of mediators known collectively as mtDAMPs, including formyl and other peptides as well as mtDNA fragments (14). The latter is conspicuous in light of observational studies in human subjects showing that serum levels of mtDNA DAMPs are predictive of outcomes in critically ill, septic or severely injured patients (10–12, 15, 16). In addition, a number of experiments in animal and cell culture models show that mtDNA is elaborated into the extracellular environment by inflammatory injury and that administration of exogenously-produced mtDNA DAMPs recapitulates many of the attributes of ARDS and multi-organ failure seen in human subjects (8, 9, 17, 18).…”

Section: Discussionmentioning

confidence: 99%

Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions

Simmons

Lee²,

Pastukh

et al. 2017

Journal of Trauma and Acute Care Surgery

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Introduction Massive transfusions are accompanied by an increased incidence of a particularly aggressive and lethal form of acute lung injury (delayed TRALI) which occurs >24 hours after transfusions. In light of recent reports showing that mtDNA DAMPs are potent pro-inflammatory mediators, and that their abundance in the sera of severely injured or septic patients is predictive of clinical outcomes, we explored the idea that mtDNA DAMPs are present in transfusion products and are associated with the occurrence of delayed TRALI. Methods We prospectively enrolled fourteen consecutive severely injured patients that received greater than three units of blood transfusion products and determined if the total amount of mtDNA DAMPs delivered during transfusion correlated with serum mtDNA DAMPs measured after the last transfusion, and whether the quantity of mtDNA DAMPs in the serum predicted development of ARDS. Results We found detectable levels of mtDNA DAMPs in PRBCs (3±0.4 ng/mL), FFP (213.7± 65 ng/mL), and platelets (94.8±69.2), with the latter two transfusion products containing significant amounts of mtDNA fragments. There was a linear relationship between the mtDNA DAMPs given during transfusion and the serum concentration of mtDNA fragments (R2=0.0.74, p<0.01). The quantity of mtDNA DAMPs in serum measured at 24 hours after transfusion predicted the occurrence of ARDS (9.9±1.4 vs 3.3±0.9, p<0.01). Conclusion These data show that FFP and platelets contain large amounts of extracellular mtDNA, that the amount of mtDNA DAMPs administered during transfusion may be a determinant of serum mtDNA DAMP levels, and that serum levels of mtDNA DAMPs after multiple transfusions may predict the development of ARDS. Collectively, these findings support the idea that mtDNA DAMPs in transfusion products significantly contribute to the incidence of ARDS after massive transfusions. Level of Evidence Level 1. (Prognostic and Diagnostic).

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“…As a response, the body initiates systemic inflammation [13]. Interestingly, high circulating levels of mtDNA along with increased TLR9 expression have been used in recent clinical studies as a predictor of mortality in critically ill intensive care unit (ICU) patients [14]. Furthermore, urinary mtDNA has been used as a biomarker of mitochondrial damage in acute kidney injury [15], and circulating mtDNA could play an important role in assessing cardiac graft damage from IR injury in a similar way.…”

Section: Ischemia-reperfusion Injurymentioning

confidence: 98%

The Critical Role of Bioenergetics in Donor Cardiac Allograft Preservation

Schipper

Marsh

Ferng

et al. 2016

J. of Cardiovasc. Trans. Res.

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The traditional philosophy of ex vivo organ preservation has been to limit metabolic activity by storing organs in hypothermic, static conditions. This methodology cannot provide longevity of hearts for more than 4-6 h and is thereby insufficient to expand the number of available organs. Albeit at lower rate, the breakdown of ATP still occurs during hypothermia. Furthermore, cold static preservation does not prevent the permanent damage that occurs upon reperfusion known as ischemia-reperfusion (IR) injury. This damage is caused by increased reactive oxygen species (ROS) production in combination with mitochondrial permeability transition pore (mPTP) opening, highlighting the importance of mitochondria in ischemic storage. There has recently been a major paradigm shift in the field, with emerging research supporting changes in traditional storage approaches. Novel research suggests achieving metabolic homeostasis instead of attempting to limit metabolic activity which reduces IR injury and improves graft preservation. Maintaining high ATP levels and circumventing cold organ storage would be a much more sophisticated standard for organ storage and should be the focus of future research in organ preservation. Given the link between mPTP, Ca2(+), and ROS, managing Ca2(+) influx into the mitochondria during conditioning might be the next critical step towards preventing irreversible IR injury.

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Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients

Abstract: Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.

Cited by 67 publications

References 23 publications

Autophagy in Pulmonary Diseases

Autophagy in Pulmonary Diseases

Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions

The Critical Role of Bioenergetics in Donor Cardiac Allograft Preservation

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