ABSTRACT
The flux of Ca(2+) from the endoplasmic reticulum (ER) to mitochondria regulates mitochondria metabolism. Within tumor tissue, mitochondria metabolism is frequently repressed, leading to chemotherapy resistance and increased growth of the tumor mass. Therefore, altered ER-mitochondria Ca(2+) flux could be a cancer hallmark, but only a few regulatory proteins of this mechanism are currently known. One candidate is the redox-sensitive oxidoreductase TMX1 that is enriched on the mitochondria-associated membrane (MAM), the site of ER-mitochondria Ca(2+) flux. Our findings demonstrate that cancer cells with low TMX1 exhibit increased ER Ca(2+), accelerated cytosolic Ca(2+) clearance, and reduced Ca(2+) transfer to mitochondria. Thus, low levels of TMX1 reduce ER-mitochondria contacts, shift bioenergetics away from mitochondria, and accelerate tumor growth. For its role in intracellular ER-mitochondria Ca(2+) flux, TMX1 requires its thioredoxin motif and palmitoylation to target to the MAM. As a thiol-based tumor suppressor, TMX1 increases mitochondrial ATP production and apoptosis progression.
Subject(s)
Calcium Signaling , Endoplasmic Reticulum/metabolism , Membrane Proteins/metabolism , Mitochondria/metabolism , Neoplasms/metabolism , Sulfhydryl Compounds/metabolism , Thioredoxins/metabolism , Calcium/metabolism , Cell Proliferation/drug effects , Energy Metabolism , Glucose/pharmacology , HeLa Cells , Humans , Lipoylation , Mitochondrial Membranes/metabolism , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Amyloid-ß (Aß) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via ß- and x03B3;-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aß levels which, in turn, contribute to neuronal loss and development of AD. OBJECTIVES: In this study, we seek to determine what effect Aß has on APP processing in cultured astrocytes. METHODS: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aß1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and ßCTF, and Aß1-40. In conjunction with these experiments, we examined the relative levels and activity of ß- and x03B3;-secretases in Aß-treated astrocytes. RESULTS: We report here that Aß1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aß1-40 in a time-dependent manner. CONCLUSIONS: These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Aß-related peptides.
