Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage.

Dysfunction of endothelial cells (ECs) lining the inner surface of blood vessels are causative for a number of diseases. Hence, the ability to therapeutically modulate gene expression within ECs is of high therapeutic value in treating diseases such as those associated with lung edema. mRNAs formulated with lipid nanoparticles (LNPs) have emerged as a new drug modality to induce transient protein expression for modulating disease-relevant signal transduction pathways.

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.

Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma.

Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels.

Homeostatic functions of BCL-2 proteins beyond apoptosis.

Since its introduction in 1930 by physiologist Walter Bradford Cannon, the concept of homeostasis remains the cardinal tenet of biologic regulation. Cells have evolved a highly integrated network of control mechanisms, including positive and negative feedback loops, to safeguard homeostasis in face of a wide range of stimuli. Such control mechanisms ultimately orchestrate cell death, division and repair in a manner concordant with cellular energy and ionic balance to achieve proper biologic fitness.

SLP-2 is required for stress-induced mitochondrial hyperfusion.

Mitochondria are dynamic organelles, the morphology of which results from an equilibrium between two opposing processes, fusion and fission. Mitochondrial fusion relies on dynamin-related GTPases, the mitofusins (MFN1 and 2) in the outer mitochondrial membrane and OPA1 (optic atrophy 1) in the inner mitochondrial membrane. Apart from a role in the maintenance of mitochondrial DNA, little is known about the physiological role of mitochondrial fusion.

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).

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.

TRB3 is a PI 3-kinase dependent indicator for nutrient starvation.

We have identified TRB3, a human homologue of Drosophila tribbles, as a novel transcriptional target of phosphatidylinositol (PI) 3-kinase. TRB3 expression is remarkably reduced in prostate cancer PC-3 cells after inhibition of PI 3-kinase. TRB3 expression is furthermore controlled by nutrient supplies: Both the lack of glucose or amino acids results in a substantial increase in TRB3 protein levels in a PI 3-kinase-dependent manner.

The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells.

Mitochondria are dynamic organelles that change morphology by controlled fission and fusion events. Mitochondrial fission is regulated by a conserved protein complex assembled at the outer membrane. Human MTP18 is a novel nuclear-encoded mitochondrial membrane protein, implicated in controlling mitochondrial fission.

REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase.

Cancer cells frequently evade apoptosis during tumorigenesis by acquiring mutations in apoptotic regulators. Chronic activation of the PI 3-kinase-Akt pathway through loss of the tumor suppressor PTEN is one mechanism by which these cells can gain increased protection against apoptosis. We report here that REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells (PC-3).

Knockdown of MTP18, a novel phosphatidylinositol 3-kinase-dependent protein, affects mitochondrial morphology and induces apoptosis.

We identified a novel human cDNA encoding a mitochondrial protein, MTP18 (mitochondrial protein, 18 kDa) as a transcriptional downstream target of phosphatidylinositol (PI) 3-kinase signaling. We demonstrate that MTP18 mRNA as well as protein expression is dependent on PI 3-kinase activity. Confocal microscopy and biochemical fractionation revealed a mitochondrial localization of MTP18.