Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown.

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.

Unlabelled: Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre , abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown.

Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure.

Implications of Sphingolipids on Aging and Age-Related Diseases.

Aging is a process leading to a progressive loss of physiological integrity and homeostasis, and a primary risk factor for many late-onset chronic diseases. The mechanisms underlying aging have long piqued the curiosity of scientists. However, the idea that aging is a biological process susceptible to genetic manipulation was not well established until the discovery that the inhibition of insulin/IGF-1 signaling extended the lifespan of .

Rapid affinity purification of intracellular organelles using a twin strep tag.

Cells are internally organized into compartmentalized organelles that execute specialized functions. To understand the functions of individual organelles and their regulations, it is critical to resolve the compositions of individual organelles, which relies on a rapid and efficient isolation method for specific organellar populations. Here, we introduce a robust affinity purification method for rapid isolation of intracellular organelles (e.

360-degree tabletop electronic holographic display.

We demonstrate a tabletop holographic display system for simultaneously serving continuous parallax 3.2-inch 360-degree three-dimensional holographic image content to multiple observers at a 45-degree oblique viewing circumference. To achieve this, localized viewing windows are to be seamlessly generated on the 360-degree viewing circumference.

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis.

During neurodegenerative disease, the toxic accumulation of aggregates and misfolded proteins is often accompanied with widespread changes in peripheral metabolism, even in cells in which the aggregating protein is not present. The mechanism by which the central nervous system elicits a distal reaction to proteotoxic stress remains unknown. We hypothesized that the endocrine communication of neuronal stress plays a causative role in the changes in mitochondrial homeostasis associated with proteotoxic disease states.

Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response.

Defects in mitochondrial metabolism have been increasingly linked with age-onset protein-misfolding diseases such as Alzheimer's, Parkinson's, and Huntington's. In response to protein-folding stress, compartment-specific unfolded protein responses (UPRs) within the ER, mitochondria, and cytosol work in parallel to ensure cellular protein homeostasis. While perturbation of individual compartments can make other compartments more susceptible to protein stress, the cellular conditions that trigger cross-communication between the individual UPRs remain poorly understood.

A kinetic aggregation assay allowing selective and sensitive amyloid-β quantification in cells and tissues.

The process of amyloid-β (Aβ) fibril formation is genetically and pathologically linked to Alzheimer's disease (AD). Thus, a selective and sensitive method for quantifying Aβ fibrils in complex biological samples allows a variety of hypotheses to be tested. Herein, we report the basis for a quantitative in vitro kinetic aggregation assay that detects seeding-competent Aβ aggregates in mammalian cell culture media, in Caenorhabditis elegans lysate, and in mouse brain homogenate.

Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity.

Fibrillar protein aggregates are the major pathological hallmark of several incurable, age-related, neurodegenerative disorders. These aggregates typically contain aggregation-prone pathogenic proteins, such as amyloid-beta in Alzheimer's disease and alpha-synuclein in Parkinson's disease. It is, however, poorly understood how these aggregates are formed during cellular aging.

PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1.

During apoptosis, cytochrome c is released from mitochondria to the cytosol, where it binds Apaf-1. The Apaf-1/cytochrome c complex then oligomerizes either into heptameric caspase-9-activating apoptosome, which subsequently activates caspase-3 and caspase-7, or bigger inactive aggregates, depending on the availability of nucleotide dATP/ATP. A tumor suppressor protein, PHAPI, enhances caspase-9 activation by promoting apoptosome formation through an unknown mechanism.

Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1.

Apoptosis in metazoans is executed by a group of intracellular proteases named caspases. One of the caspase-activating pathways in mammals is initiated by the release of cytochrome c from mitochondria to cytosol, where it binds to Apaf-1 to form a procaspase-9-activating heptameric protein complex named apoptosome. We report here the reconstitution of this pathway with purified recombinant Apaf-1, procaspase-9, procaspase-3, and cytochrome c from horse heart.

R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway.

The RNA interference (RNAi) pathway is initiated by processing long double-stranded RNA into small interfering RNA (siRNA). The siRNA-generating enzyme was purified from Drosophila S2cells and consists of two stoichiometric subunits: Dicer-2(DCR-2) and a previously unknown protein that we named R2D2. R2D2 is homologous to the Caenorhabditis elegans RNAi protein RDE-4.

Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway.

A small molecule, alpha-(trichloromethyl)-4-pyridineethanol (PETCM), was identified by high-throughput screening as an activator of caspase-3 in extracts of a panel of cancer cells. PETCM was used in combination with biochemical fractionation to identify a pathway that regulates mitochondria-initiated caspase activation. This pathway consists of tumor suppressor putative HLA-DR-associated proteins (PHAP) and oncoprotein prothymosin-alpha (ProT).