Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1

m-AAA proteases cleave OPA1 to ensure a balance of long and short OPA1 isoforms, whereas cleavage by OMA1 causes an accumulation of the short OPA1 variants. (See also companion paper from Head et al. in this issue.

Geophysik und 3D-Modellierung im Osterzgebirge: Voruntersuchungen zur Neubaustrecke Dresden–Prag: Ergebnisse der Forschungsberichte: Geophysikalische Untersuchungen an der Struktur Börnersdorf/Osterzgebirge zur Klärung der tektonischen Situation, 3D-Modellierung der Struktur Börnersdorf sowie der Neubaustrecke Dresden–Prag im Osterzgebirge

Der Bericht liefert einen Überblick über die geologischen Gegebenheiten entlang der geplanten Schienenneubaustrecke zwischen Dresden und Prag, die als Teilabschnitt des Middle-East-Korridors zum Trans-Europäischen Netz gehört. Er beinhaltet ein geologisches 3D-Modell entlang der Trasse, die Ergebnisse geophysikalischer Untersuchungen im Bereich der Struktur Börnersdorf und Ergebnisse geotechnischer Untersuchungen an ausgewählten Punkten. Die Veröffentlichung richtet sich an Ingenieur- und Planungsbüros, Forschungs- und Lehreinrichtungen sowie Behörden

SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability

Stomatin is a member of a large family of proteins including prohibitins, HflK/C, flotillins, mechanoreceptors and plant defense proteins, that are thought to play a role in protein turnover. Using different proteomic approaches, we and others have identified SLP-2, a member of the stomatin gene family, as a component of the mitochondria. In this study, we show that SLP-2 is strongly associated with the mitochondrial inner membrane and that it interacts with prohibitins. Depleting HeLa cells of SLP-2 lead to increased proteolysis of prohibitins and of subunits of the respiratory chain complexes I and IV. Further supporting the role of SLP-2 in regulating the stability of specific mitochondrial proteins, we found that SLP-2 is up-regulated under conditions of mitochondrial stress leading to increased protein turnover. These data indicate that SLP-2 plays a role in regulating the stability of mitochondrial proteins including prohibitins and subunits of respiratory chain complexes

Preventing Mitochondrial Fission Impairs Mitochondrial Function and Leads to Loss of Mitochondrial DNA

Mitochondria form a highly dynamic tubular network, the morphology of which is regulated by frequent fission and fusion events. However, the role of mitochondrial fission in homeostasis of the organelle is still unknown. Here we report that preventing mitochondrial fission, by down-regulating expression of Drp1 in mammalian cells leads to a loss of mitochondrial DNA and a decrease of mitochondrial respiration coupled to an increase in the levels of cellular reactive oxygen species (ROS). At the cellular level, mitochondrial dysfunction resulting from the lack of fission leads to a drop in the levels of cellular ATP, an inhibition of cell proliferation and an increase in autophagy. In conclusion, we propose that mitochondrial fission is required for preservation of mitochondrial function and thereby for maintenance of cellular homeostasis

A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2

Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-highthroughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy

Geophysik und 3D-Modellierung im Osterzgebirge: Voruntersuchungen zur Neubaustrecke Dresden–Prag: Ergebnisse der Forschungsberichte: Geophysikalische Untersuchungen an der Struktur Börnersdorf/Osterzgebirge zur Klärung der tektonischen Situation, 3D-Modellierung der Struktur Börnersdorf sowie der Neubaustrecke Dresden–Prag im Osterzgebirge

Der Bericht liefert einen Überblick über die geologischen Gegebenheiten entlang der geplanten Schienenneubaustrecke zwischen Dresden und Prag, die als Teilabschnitt des Middle-East-Korridors zum Trans-Europäischen Netz gehört. Er beinhaltet ein geologisches 3D-Modell entlang der Trasse, die Ergebnisse geophysikalischer Untersuchungen im Bereich der Struktur Börnersdorf und Ergebnisse geotechnischer Untersuchungen an ausgewählten Punkten. Die Veröffentlichung richtet sich an Ingenieur- und Planungsbüros, Forschungs- und Lehreinrichtungen sowie Behörden