title: TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.
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.
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Arun
authors: 0000-0001-6972-6078
authors: A
authors: Raturi
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Tomás
authors: 0000-0002-5218-2286
authors: T
authors: Gutiérrez
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Carolina
authors: 0000-0001-5003-9489
authors: C
authors: Ortiz-Sandoval
authors: Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Araya
authors: 0000-0002-9606-8557
authors: A
authors: Ruangkittisakul
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Maria Sol
authors: MS
authors: Herrera-Cruz
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Jeremy P
authors: 0000-0002-3309-1397
authors: JP
authors: Rockley
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Kevin
authors: K
authors: Gesson
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Dimitar
authors: 0000-0003-4629-5919
authors: D
authors: Ourdev
authors: Department of Anesthesiology and Pain Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Phing-How
authors: PH
authors: Lou
authors: Department of Anesthesiology and Pain Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Eliana
authors: E
authors: Lucchinetti
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Nasser
authors: 0000-0002-4128-0980
authors: N
authors: Tahbaz
authors: Department of Anesthesiology and Pain Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Michael
authors: M
authors: Zaugg
authors: 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.
authors: Shairaz
authors: S
authors: Baksh
authors: Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
authors: Klaus
authors: 0000-0001-7952-762X
authors: K
authors: Ballanyi
authors: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada thomas.simmen@ualberta.ca.
authors: Thomas
authors: 0000-0002-2350-2965
authors: T
authors: Simmen
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004734:Energy Metabolism; D005947:Glucose / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D054878:Lipoylation; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C425307:TMX1 protein, human; D013879:Thioredoxins; D005947:Glucose; D002118:Calcium