bims-mitinf 2019-01-13 papers

JCI Insight. 2019 Jan 10. pii: 120722. [Epub ahead of print]4(1):

SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury.

Deepali Kurundkar, Ashish R Kurundkar, Nathaniel B Bone, Eugene J Becker, Wanqu Liu, Balu Chacko, Victor Darley-Usmar, Jaroslaw W Zmijewski, Victor J Thannickal.

Acute lung injury (ALI) is characterized by exuberant proinflammatory responses and mitochondrial dysfunction. However, the link between mitochondrial dysfunction and inflammation in ALI is not well understood. In this report, we demonstrate a critical role for the mitochondrial NAD+-dependent deacetylase, sirtuin-3 (SIRT3), in regulating macrophage mitochondrial bioenergetics, ROS formation, and proinflammatory responses. We found that SIRT3 expression was significantly diminished in lungs of mice subjected to LPS-induced ALI. SIRT3-deficient mice (SIRT3-/-) develop more severe ALI compared with wild-type controls (SIRT3+/+). Macrophages obtained from SIRT3-/- mice show significant alterations in mitochondrial bioenergetic and redox homeostasis, in association with a proinflammatory phenotype characterized by NLRP3 inflammasome activation. The SIRT3 activator viniferin restored macrophage bioenergetic function in LPS-treated macrophages. Viniferin also reduced NLRP3 activation and the production of proinflammatory cytokines, effects that were absent in SIRT3-/- macrophages. In-vivo administration of viniferin reduced production of inflammatory mediators TNF-α, MIP-2, IL-6, IL-1β, and HMGB1, and diminished neutrophil influx and severity of endotoxin-mediated ALI; this protective effect of vinferin was abolished in SIRT3-/- mice. Taken together, our results show that the induction/activation of SIRT3 may serve as a new therapeutic strategy in ALI by modulating cellular bioenergetics, controlling inflammatory responses, and reducing the severity of lung injury.

Keywords: Innate immunity; Macrophages; Metabolism; Pulmonology

DOI: https://doi.org/10.1172/jci.insight.120722

Sci Signal. 2019 Jan 08. pii: eaat9900. [Epub ahead of print]12(563):

Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells.

Souvarish Sarkar, Dharmin Rokad, Emir Malovic, Jie Luo, Dilshan S Harischandra, Huajun Jin, Vellareddy Anantharam, Xuemei Huang, Mechelle Lewis, Arthi Kanthasamy, Anumantha G Kanthasamy.

Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn2+ had similar effects in brain microglial cells. Furthermore, Mn2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1β than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

DOI: https://doi.org/10.1126/scisignal.aat9900

F1000Res. 2018 ;pii: F1000 Faculty Rev-1889. [Epub ahead of print]7

Recent advances in understanding inhibitor of apoptosis proteins.

Najoua Lalaoui, David Lawrence Vaux.

The inhibitor of apoptosis proteins (IAPs) are a family of proteins that were chiefly known for their ability to inhibit apoptosis by blocking caspase activation or activity. Recent research has shown that cellular IAP1 (cIAP1), cIAP2, and X-linked IAP (XIAP) also regulate signaling by receptors of the innate immune system by ubiquitylating their substrates. These IAPs thereby act at the intersection of pathways leading to cell death and inflammation. Mutation of IAP genes can impair tissue homeostasis and is linked to several human diseases. Small-molecule IAP antagonists have been developed to treat certain malignant, infectious, and inflammatory diseases. Here, we will discuss recent advances in our understanding of the functions of cIAP1, cIAP2, and XIAP; the consequences of their mutation or dysregulation; and the therapeutic potential of IAP antagonist drugs.

Keywords: IAP; cell death; inflammation; innate receptors signalling; smac-mimetic

DOI: https://doi.org/10.12688/f1000research.16439.1

Nature. 2019 Jan 09.

Mitochondrial complex III is essential for suppressive function of regulatory T cells.

Samuel E Weinberg, Benjamin D Singer, Elizabeth M Steinert, Carlos A Martinez, Manan M Mehta, Inmaculada Martínez-Reyes, Peng Gao, Kathryn A Helmin, Hiam Abdala-Valencia, Laura A Sena, Paul T Schumacker, Laurence A Turka, Navdeep S Chandel.

Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

DOI: https://doi.org/10.1038/s41586-018-0846-z

Cell Rep. 2019 Jan 08. pii: S2211-1247(18)31980-6. [Epub ahead of print]26(2): 338-345.e6

A Mammalian Mitophagy Receptor, Bcl2-L-13, Recruits the ULK1 Complex to Induce Mitophagy.

Tomokazu Murakawa, Koji Okamoto, Shigemiki Omiya, Manabu Taneike, Osamu Yamaguchi, Kinya Otsu.

Degradation of mitochondria by selective autophagy, termed mitophagy, contributes to the control of mitochondrial quality. Bcl2-L-13 is a mammalian homolog of Atg32, which is an essential mitophagy receptor in yeast. However, the molecular machinery involved in Bcl2-L-13-mediated mitophagy remains to be elucidated. Here, we show that the ULK1 (unc-51-like kinase) complex is required for Bcl2-L-13 to process mitophagy. Screening of a series of yeast Atg mutants revealed that a different set of ATG genes is used for Bcl2-L-13- and Atg32-mediated mitophagy in yeast. The components of the Atg1 complex essential for starvation-induced autophagy were indispensable in Bcl2-L-13-, but not Atg32-mediated, mitophagy. The ULK1 complex, a counterpart of the Atg1 complex, is necessary for Bcl2-L-13-mediated mitophagy in mammalian cells. We propose a model where, upon mitophagy induction, Bcl2-L-13 recruits the ULK1 complex to process mitophagy and the interaction of LC3B with ULK1, as well as Bcl2-L-13, is important for the mitophagy.

Keywords: Atg32; Bcl2-L-13; mitochondria; mitophagy

DOI: https://doi.org/10.1016/j.celrep.2018.12.050

Eur Heart J Acute Cardiovasc Care. 2019 Jan 11. 2048872618823405

Release of mitochondrial DNA is associated with mortality in severe acute heart failure.

Konstantin A Krychtiuk, Raphael Wurm, Sarah Ruhittel, Max Lenz, Kurt Huber, Johann Wojta, Gottfried Heinz, Martin Hülsmann, Walter S Speidl.

BACKGROUND:: Inflammation is regarded as an important trigger for disease progression in heart failure. Particularly in severe acute heart failure, tissue hypoxia may lead to cellular damage and the release of intracellular mitochondrial DNA, which acts as an activator of the immune system due to its resemblance to bacterial DNA. It may therefore serve as a mediator of disease progression. The aim of this study was to determine circulating levels of mitochondrial DNA and its association with mortality in patients with heart failure in different presentations.
METHODS:: Plasma levels of circulating mitochondrial DNA were measured in 90 consecutive patients with severe acute heart failure admitted to our medical intensive care unit as well as 109 consecutive chronic heart failure patients.
RESULTS:: In patients admitted to our medical intensive care unit (median age 64 (49-74) years, median NT-pro-brain natriuretic peptide 4986 (1525-23,842) pg/mL, 30-day survival 64.4%), mitochondrial DNA levels were significantly higher in patients who died within 30 days after intensive care unit admission, and patients with plasma levels of mitochondrial DNA in the highest quartile had a 3.4-fold increased risk ( P=0.002) of dying independent of renal function, vasopressor use and NT-pro-brain natriuretic peptide, troponin T, lactate levels or CardShock and acute physiology and chronic health evaluation II score. However, mitochondrial DNA did not provide incremental prognostic accuracy on top of the current gold standard acute physiology and chronic health evaluation II. Patients with severe acute heart failure showed significantly higher mitochondrial DNA levels ( P<0.005) as compared to patients with chronic heart failure. In these patients, mitochondrial DNA levels were associated with the New York Heart Association functional class but were not associated with outcome.
CONCLUSIONS:: The release of mitochondrial DNA into the circulation is associated with mortality in patients with severe acute heart failure but not in patients with chronic heart failure. The release of mitochondrial DNA may therefore play a role within the pathophysiology of acute heart failure, which warrants further research. However, the use of mitochondrial DNA as a biomarker for risk stratification in these patients is of limited utility.

Keywords: Acute heart failure; chronic heart failure; inflammation; mitochondrial DNA

DOI: https://doi.org/10.1177/2048872618823405