title: Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis.
abstract: During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane (MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only proteins such as tBID, together with lipids of the MOM, are thought to play a key role in BAX and BAK activation. In particular, cardiolipin (CL) has been shown to stimulate tBID-induced BAX activation in vitro. However, it is still unclear whether this process also relies on CL in the cell, or whether it is more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To address this issue, we deleted both alleles of cardiolipin synthase in human HCT116 cells by homologous recombination, which resulted in a complete absence of CL. The CL-deficient cells were fully viable in glucose but displayed impaired oxidative phosphorylation and an inability to grow in galactose. Using these cells, we found that CL was not required for either tBID-induced BAX activation, or for apoptosis in response to treatment with TRAIL. Downregulation of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to mitochondria in apoptotic conditions. However, when both CL and MTCH2 were depleted, a significant reduction in tBID recruitment was observed, suggesting that in HCT116 cells, CL and MTCH2 can have redundant functions in this process.
authors.affiliation: Department of Cell Biology, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Raemy
authors.affiliation: Department of Cell Biology, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Montessuit
authors.affiliation: Department of Cell Biology, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Pierredon
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.|Biosystems Data Analysis Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, AZ, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Department of Cell Biology, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: J-C
authors.initials: JC
authors.lastname: Martinou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002308:Cardiolipins / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005690:Galactose / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008055:Lipids / Q000032:analysis / Q000302:isolation & purification; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C475077:CRLS1 protein, human; D002308:Cardiolipins; D008055:Lipids; C502207:MTCH2 protein, human; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D005947:Glucose; D005690:Galactose