The role of mitochondria in rheumatic diseases.

The mitochondrion is an intracellular organelle thought to originate from endosymbiosis between an ancestral eukaryotic cell and an α-proteobacterium. Mitochondria are the powerhouses of the cell, and can control several important processes within the cell, such as cell death. Conversely, dysregulation of mitochondria possibly contributes to the pathophysiology of several autoimmune diseases. Defects in mitochondria can be caused by mutations in the mitochondrial genome or by chronic exposure to pro-inflammatory cytokines, including type I interferons. Following the release of intact mitochondria or mitochondrial components into the cytosol or the extracellular space, the bacteria-like molecular motifs of mitochondria can elicit pro-inflammatory responses by the innate immune system. Moreover, antibodies can target mitochondria in autoimmune diseases, suggesting an interplay between the adaptive immune system and mitochondria. In this Review, we discuss the roles of mitochondria in rheumatic diseases such as systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis. An understanding of the different contributions of mitochondria to distinct rheumatic diseases or manifestations could permit the development of novel therapeutic strategies and the use of mitochondria-derived biomarkers to inform pathogenesis.

Atomistic Assessment of Melting Point Depression and Enhanced Interfacial Diffusion of Cu in Confinement with AlN.

The continuing trend in heterogeneous integration (i.e., miniaturization and diversification of devices and components) requires a fundamental understanding of the phase stability and diffusivity of nanoconfined metals in functional nanoarchitectures, such as nanomultilayers (NMLs). Nanoconfinement effects, such as interfacial melting and anomalous fast interfacial diffusion, offer promising engineering tools to enhance the reaction kinetics at low temperatures for targeted applications in the fields of joining, solid-state batteries, and low-temperature sintering technologies. In the present study, the phase stability and atomic mobility of confined metals in Cu/AlN NMLs were investigated by molecular dynamics, with the interatomic potential compared to the ab initio calculations of the Cu/AlN interface adhesion energy. Simulations of the structural evolution of Cu/AlN nanomultilayers upon heating in dependence on the Cu nanolayer thickness demonstrate the occurrence of interfacial premelting, a melting point depression, as well as extraordinary fast solid-state diffusion of confined Cu atoms along the defective heterogeneous interfaces. The model predictions rationalize recent experimental observations of premelting and anomalous fast interface diffusion of nanoconfined metals in nanostructured Cu/AlN brazing fillers at strikingly low temperatures.

Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus.

OBJECTIVE: Mitochondria are organelles that exhibit several bacterial features, such as a double-stranded genome with hypomethylated CpG islands, formylated proteins, and cardiolipin-containing membranes. In systemic lupus erythematosus (SLE), mitochondria and their inner components are released into the extracellular space, potentially eliciting a proinflammatory response from the immune system. While cardiolipin and mitochondrial DNA and RNA are confirmed targets of autoantibodies, other antigenic mitochondrial proteins in SLE remain to be identified. The present study was undertaken to characterize the protein repertoire recognized by antimitochondrial antibodies (AMAs) in patients with SLE. METHODS: Using shotgun proteomic profiling, we identified 1,345 proteins, 431 of which were associated with the mitochondrial proteome. Immunoreactivities to several of these candidate proteins were assessed in serum samples from a local cohort (n = 30 healthy donors and 87 patients with SLE) using enzyme-linked immunosorbent assay, and further analyzed for associations with demographic and disease characteristics. RESULTS: We determined that IgG antibodies to the complement component C1q binding protein were significantly elevated in the patients with SLE (P = 0.049) and were also associated with lupus anticoagulant positivity (P = 0.049). Elevated levels of IgG antibodies against mitochondrial protein mitofusin 1 (MFN-1) were promising predictors of SLE diagnosis in our cohort (adjusted odds ratio 2.99 [95% confidence interval 1.39-6.43], P = 0.0044). Moreover, increased levels of anti-MFN-1 were associated with the presence of antiphospholipids (P = 0.011) and anti-double-stranded DNA (P = 0.0005). CONCLUSION: In this study, we characterized the mitochondrial repertoire targeted by AMAs in the setting of SLE. Our results indicate that autoantibodies can recognize secreted and/or surface proteins of mitochondrial origin. Profiling of the AMA repertoire in large prospective cohorts may improve our knowledge of mitochondrial biomarkers and their usefulness for patient stratification.

Molecular genetics of alcohol dependence and related endophenotypes.

Alcohol dependence is a worldwide public health problem, and involves both environmental and genetic vulnerability factors. The heritability of alcohol dependence is rather high, ranging between 50% and 60%, although alcohol dependence is a polygenic, complex disorder.Genome-wide scans on large cohorts of multiplex families, including the collaborative study on genetics of alcoholism (COGA), emphasized the role of many chromosome regions and some candidate genes. The genes encoding the alcohol-metabolizing enzymes, or those involved in brain reward pathways, have been involved. Since dopamine is the main neurotransmitter in the reward circuit, genes involved in the dopaminergic pathway represent candidates of interest. Furthermore, gamma-amino-butyric acid (GABA) neurotransmitter mediates the acute actions of alcohol and is involved in withdrawal symptomatology. Numerous studies showed an association between variants within GABA receptors genes and the risk of alcohol dependence.In accordance with the complexity of the "alcohol dependence" phenotype, another field of research, related to the concept of endophenotypes, received more recent attention. The role of vulnerability genes in alcohol dependence is therefore re-assessed focusing on different phenotypes and endophenotypes. The latter include brain oscillations, EEG alpha and beta variants and alpha power, and amplitude of P300 amplitude elicited from a visual oddball task.Recent enhancement on global characterizations of the genome by high-throughput approach for genotyping of polymorphisms and studies of transcriptomics and proteomics in alcohol dependence is also reviewed.