Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS).

Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production.

Amyloid Fibrils of the s36 Protein Modulate the Morphogenesis of Eggshell.

is the oldest classic model object in developmental genetics. It may seem that various structures of the fruit fly at all developmental stages have been well studied and described. However, recently we have shown that some specialized structures of the eggshell contain an amyloid fibril network.

Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics.

Alternative oxidase (AOX) is an enzyme that transfers electrons from reduced quinone directly to oxygen without proton translocation. When AOX from Ciona intestinalis is xenotopically expressed in mice, it can substitute the combined electron-transferring activity of mitochondrial complexes III/IV. Here, we used brain mitochondria from AOX-expressing mice with such a chimeric respiratory chain to study respiratory control bioenergetic mechanisms.

Sex-dependent differences in macaque brain mitochondria.

Mitochondrial bioenergetics in females and males is different. However, whether mitochondria from male and female brains display differences in enzymes of oxidative phosphorylation remains unknown. Therefore, we characterized mitochondrial complexes from the brains of male and female macaques (Macaca mulatta).

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity.

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously.

Amyloids and prions in the light of evolution.

Functional amyloids have been identified in a wide variety of organisms including bacteria, fungi, plants, and vertebrates. Intracellular and extracellular amyloid fibrils of different proteins perform storage, protective, structural, and regulatory functions. The structural organization of amyloid fibrils determines their unique physical and biochemical properties.

Search and Identification of Amyloid Proteins.

Amyloids are fibrillar proteins with a cross-β structure. Pathological amyloids are associated with the development of a number of incurable diseases, while functional amyloids regulate vital processes. The detection of unknown amyloids in living objects is a difficult task, and therefore the question of the prevalence and biological significance of amyloids remains open.

Effect of metformin on intact mitochondria from liver and brain: Concept revisited.

Metformin is an antihyperglycemic drug which is being examined as a repurposed treatment for cardiovascular disease for individuals without diabetes mellitus. Despite evidence that mitochondrial respiratory complex I is a target of metformin and inhibition of the enzyme is one of the mechanisms of its therapeutic actions, no systematic studies of the metformin effect on intact mitochondria have been reported. In the presented paper, we described the effect of metformin on respiration and ROS release by intact mitochondria from the liver and brain.

Amyloid Properties of the FXR1 Protein Are Conserved in Evolution of Vertebrates.

Functional amyloids are fibrillary proteins with a cross-β structure that play a structural or regulatory role in pro- and eukaryotes. Previously, we have demonstrated that the RNA-binding FXR1 protein functions in an amyloid form in the rat brain. This RNA-binding protein plays an important role in the regulation of long-term memory, emotions, and cancer.

Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension.

Background: Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib.

Methods: Seralutinib and imatinib potency and selectivity were compared.

Distribution of HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 allele frequencies in patients with COVID-19 bilateral pneumonia in Russians, living in the Chelyabinsk region (Russia).

In this population-based case-control study conducted in the Chelyabinsk region of Russia, we examined the distribution of HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, in a group of 100 patients with confirmed COVID-19 bilateral pneumonia. Typing was performed by NGS and statistical calculations were carried out with the Arlequin program. HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were compared between patients with COVID-19 and 99 healthy controls.

How many molecules of mitochondrial complex I are in a cell?

Mitochondrial complex I is the only enzyme responsible for oxidation of matrix NADH and regeneration of NAD for catabolism. Nuclear and mtDNA mutations, assembly impairments, and enzyme damage are implicated in inherited diseases, ischemia-reperfusion injury, neurodegeneration, and tumorogenesis. Here we introduce a novel method to measure the absolute content of complex I.

Model of Epidemic Kinetics with a Source on the Example of Moscow.

A new theoretical model of epidemic kinetics is considered, which uses elements of the physical model of the kinetics of the atomic level populations of an active laser medium as follows: a description of states and their populations, transition rates between states, an integral operator, and a source of influence. It is shown that to describe a long-term epidemic, it is necessary to use the concept of the source of infection. With a model constant source of infection, the epidemic, in terms of the number of actively infected people, goes to a stationary regime, which does not depend on the population size and the characteristics of quarantine measures.

Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial Ca-Independent Phospholipase Aγ in the Brain.

Mitochondrial Ca-independent phospholipase Aγ (iPLAγ/PNPLA8) was previously shown to be directly activated by HO and release free fatty acids (FAs) for FA-dependent H transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLAγ in the brain is not completely understood.

Redox-dependent loss of flavin by mitochondria complex I is different in brain and heart.

Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-]pyrimidine scaffold. The optimization of this pyrrolo[2,3-]pyrimidine core resulted in compound , which demonstrated potent RET kinase inhibition and robust efficacy in RET-driven tumor xenografts upon multiday dosing in mice.

Quantification of NADH:ubiquinone oxidoreductase (complex I) content in biological samples.

Impairments in mitochondrial energy metabolism have been implicated in human genetic diseases associated with mitochondrial and nuclear DNA mutations, neurodegenerative and cardiovascular disorders, diabetes, and aging. Alteration in mitochondrial complex I structure and activity has been shown to play a key role in Parkinson's disease and ischemia/reperfusion tissue injury, but significant difficulty remains in assessing the content of this enzyme complex in a given sample. The present study introduces a new method utilizing native polyacrylamide gel electrophoresis in combination with flavin fluorescence scanning to measure the absolute content of complex I, as well as α-ketoglutarate dehydrogenase complex, in any preparation.

GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors.

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αβ), expressed on both MDSCs and TAMs.

Developmental window of vulnerability to white matter injury driven by sublethal intermittent hypoxemia.

Background: In the developing brain, the death of immature oligodendrocytes (OLs) has been proposed to explain a developmental window for vulnerability to white matter injury (WMI). However, in neonatal mice, chronic sublethal intermittent hypoxia (IH) recapitulates the phenotype of diffuse WMI without affecting cellular viability. This work determines whether, in neonatal mice, a developmental window of WMI vulnerability exists in the absence of OLs lineage cellular death.

Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid-Conducting SLC25 Gene Family Transporters.

Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca-independent phospholipase A2γ (iPLA2γ), is addressed to the mitochondrial matrix (or peroxisomes), where it may manifest its unique activity to cleave phospholipid side-chains from both sn-1 and sn-2 positions, consequently releasing either saturated or unsaturated fatty acids (FAs), including oxidized FAs. Moreover, iPLA2γ is directly stimulated by HO and, hence, is activated by redox signaling or oxidative stress. This redox activation permits the antioxidant synergy with mitochondrial uncoupling proteins (UCPs) or other SLC25 mitochondrial carrier family members by FA-mediated protonophoretic activity, termed mild uncoupling, that leads to diminishing of mitochondrial superoxide formation.