Mitochondrial dysfunction and its role in tissue-specific cellular stress

Mitochondrial bioenergetics require the coordination of two different and independent genomes. Mutations in either genome will affect mitochondrial functionality and produce different sources of cellular stress. Depending on the kind of defect and stress, different tissues and organs will be affected, leading to diverse pathological conditions. There is no curative therapy for mitochondrial diseases, nevertheless, there are strategies described that fight the various stress forms caused by the malfunctioning organelles. Here, we will revise the main kinds of stress generated by mutations in mitochondrial genes and outline several ways of fighting this stress

Droplet Microarray as a Powerful Platform for Seeking New Antibiotics Against Multidrug‐Resistant Bacteria

Multidrug-resistant (MDR) bacteria is a severe threat to public health. Therefore, it is urgent to establish effective screening systems for identifying novel antibacterial compounds. In this study, a highly miniaturized droplet microarray (DMA) based high-throughput screening system is established to screen over 2000 compounds for their antimicrobial properties against carbapenem-resistant Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA). The DMA consists of an array of hydrophilic spots divided by superhydrophobic borders. Due to the differences in the surface wettability between the spots and the borders, arrays of hundreds of nanoliter-sized droplets containing bacteria and different drugs can be generated for screening applications. A simple colorimetric viability readout utilizing a conventional photo scanner is developed for fast single-step detection of the inhibitory effect of the compounds on bacterial growth on the whole array. Six hit compounds, including coumarins and structurally simplified estrogen analogs are identified in the primary screening and validated with minimum inhibition concentration assay for their antibacterial effect. This study demonstrates that the DMA-based high-throughput screening system enables the identification of potential antibiotics from novel synthetic compound libraries, offering opportunities for development of new treatments against multidrug-resistant bacteria

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.Narodowe Centrum Nauki (NCN) NCN 2012/05/B/NZ3/00781NCN 2015/19/B/NZ3/03272 Deutsche Forschungsgemeinschaft (DFG) SFB1190 (P13) Fundacja na rzecz Nauki Polskiej (FNP) TEAM TECH CORE FACILITY/2016‐2/2MAB/2017/2COP/01/2016 Ministerstwo Nauki i Szkolnictwa Wyższego (MNiSW) Ideas Plus programme 000263 RCUK|Medical Research Council (MRC) MC_UU_00015/5 EC|FP7|FP7 Ideas: European Research Council (FP7 Ideas) FP7‐322424339580 Institut de France Telethon Italy GTB1200

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Uniform nomenclature for the mitochondrial contact site and cristae organizing system

The mitochondrial inner membrane contains a large protein complex that functions in inner membrane organization and formation of membrane contact sites. The complex was variably named the mitochondrial contact site complex, mitochondrial inner membrane organizing system, mitochondrial organizing structure, or Mitofilin/Fcj1 complex. To facilitate future studies, we propose to unify the nomenclature and term the complex "mitochondrial contact site and cristae organizing system" and its subunits Mic10 to Mic60

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Charakterisierung peroxisomaler Proteine aus Saccharomyces cerevisiae\textit {Saccharomyces cerevisiae}

Ein Hauptanliegen aktueller Forschung ist das generelle Verständnis des Peroxisoms als Organell. Hierbei bildet die Struktur- und Funktionsanalyse bereits identifizierter peroxisomaler Komponenten einen Schwerpunkt in der Untersuchung der Biogenese, Teilung und Vererbung des Organells. Parallel führt die Entwicklung neuer Methoden und Ansätze immer wieder zur Identifizierung von bislang unbekannten peroxisomalen Proteinen. Einen Schwerpunkt dieser Arbeit stellte die Identifizierung peroxisomaler Interaktionspartner von Pex8p, sowie Untersuchungen eines zielgerichteten Transports dieses Proteins zum Peroxisom dar. Im Weiteren wurde ein bislang unbekanntes 17 kDa Protein über einen revers genetischen Ansatz identifiziert und als peroxisomales Membranprotein charakterisiert. Abschließend konnte in dieser Arbeit gezeigt werden, dass die beiden Dynamin-verwandten Proteine Dnm1p und Vps1p die Teilung von Peroxisomen regulieren

The ALICE analysis framework for LHC Run 3

The ALICE experiment at the LHC (CERN) is currently developing a new software framework designed for Run 3: detector and software will have to cope with Pb–Pb collision rates 100 times higher than today, leading to the combination of core Online-Offline operations into a single framework called O$^2$. The analysis code is expected to run on a few large Analysis Facilities counting 20k cores and sustainin ga 100 GB/s throughput: this requires a conjoint effort between the definition of the data format, the configuration of the Analysis Facilities and the development of the Analysis Framework. We present the prototype of a new Analysis Object Data format based on timeframes and optimized for continuous readout. Such format is designed to be extensible and transported efficiently over the network. We also present the first iteration of the Analysis Framework, based on the O$^2$ Data Processing Layer and leveraging message passing across a topology of processes. We will also illustrate the implementation and benchmarking of a compatibility layer designed to mitigate the transition from the current event-oriented analysis model to the new time-oriented one. Finally, we will give a status report on the integration of the Analysis Framework and Analysis Facilities for Run 3 into the current organized analysis model in ALICE