TMX1 determines cancer cell metabolism as a thiol-based modulator of ER–mitochondria Ca2+ flux
| Autor: | Araya Ruangkittisakul, Maria Sol Herrera-Cruz, Shairaz Baksh, Eliana Lucchinetti, Thomas Simmen, Dimitar Ourdev, Michael Zaugg, Tomás Gutiérrez, Carolina Ortiz-Sandoval, Arun Raturi, Phing-How Lou, Klaus Ballanyi, Kevin Gesson, Nasser Tahbaz, Jeremy P. Rockley |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Bioenergetics Lipoylation Mitochondrion Biology Endoplasmic Reticulum Article 03 medical and health sciences Thioredoxins Palmitoylation Neoplasms Humans Calcium Signaling Sulfhydryl Compounds Research Articles Cell Proliferation Calcium signaling Endoplasmic reticulum Membrane Proteins Cell Biology Mitochondria Cell biology Glucose 030104 developmental biology Apoptosis Mitochondrial Membranes Calcium Thioredoxin Energy Metabolism Reactive Oxygen Species Intracellular HeLa Cells |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Cancer cells are critically dependent on ER–mitochondria Ca2+ flux that regulates their bioenergetics. Here, Raturi et al. identify the ER oxidoreductase TMX1 as a thiol-dependent regulator of this intracellular signaling mechanism within cancer cells. The flux of Ca2+ 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 Ca2+ 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 Ca2+ flux. Our findings demonstrate that cancer cells with low TMX1 exhibit increased ER Ca2+, accelerated cytosolic Ca2+ clearance, and reduced Ca2+ 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 Ca2+ 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. |
| Databáze: | OpenAIRE |
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