2. Academic Validation
  3. TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux

TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux

  • J Cell Biol. 2016 Aug 15;214(4):433-44. doi: 10.1083/jcb.201512077.
Arun Raturi 1,  Tomás Gutiérrez 1,  Carolina Ortiz-Sandoval 1,  Araya Ruangkittisakul 2,  Maria Sol Herrera-Cruz 1,  Jeremy P Rockley 1,  Kevin Gesson 1,  Dimitar Ourdev 1,  Phing-How Lou 3,  Eliana Lucchinetti 3,  Nasser Tahbaz 1,  Michael Zaugg 3,  Shairaz Baksh 4,  Klaus Ballanyi 2,  Thomas Simmen 5
Affiliations

Affiliations

  • 1 Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
  • 2 Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
  • 3 Department of Anesthesiology and Pain Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
  • 4 Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada Alberta Inflammatory Bowel Disease Consortium, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
  • 5 Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada thomas.simmen@ualberta.ca.
PMID: 27502484 DOI: 10.1083/jcb.201512077
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.

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