MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria.
The BH3-only BID protein (BH3-interacting domain death agonist) has a critical function in the death-receptor pathway in the liver by triggering mitochondrial outer membrane permeabilization (MOMP). Here we show that MTCH2/MIMP (mitochondrial carrier homologue 2/Met-induced mitochondrial protein), a novel truncated BID (tBID)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tBID to mitochondria. Knockout of MTCH2/MIMP in embryonic stem cells and in mouse embryonic fibroblasts hinders the recruitment of tBID to mitochondria, the activation of Bax/Bak, MOMP, and apoptosis. Moreover, conditional knockout of MTCH2/MIMP in the liver decreases the sensitivity of mice to Fas-induced hepatocellular apoptosis and prevents the recruitment of tBID to liver mitochondria both in vivo and in vitro. In contrast, MTCH2/MIMP deletion had no effect on apoptosis induced by other pro-apoptotic Bcl-2 family members and no detectable effect on the outer membrane lipid composition. These loss-of-function models indicate that MTCH2/MIMP has a critical function in liver apoptosis by regulating the recruitment of tBID to mitochondria.
Zaltsman
Yehudit
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Shachnai
Liat
L
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Yivgi-Ohana
Natalie
N
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Schwarz
Michal
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Maryanovich
Maria
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Houtkooper
Riekelt H
RH
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Vaz
Frédéric Maxime
FM
Department of Clinical Chemistry and Pediatrics, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
De Leonardis
Francesco
F
Department of Pharmaco-Biology, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Fiermonte
Giuseppe
G
Department of Pharmaco-Biology, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Palmieri
Ferdinando
F
Department of Pharmaco-Biology, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Gillissen
Bernhard
B
Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Humboldt University, 13125 Berlin, Germany.
Daniel
Peter T
PT
Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Humboldt University, 13125 Berlin, Germany.
Jimenez
Erin
E
Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, USA.
Walsh
Susan
S
Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, USA.
Koehler
Carla M
CM
Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California 90095, USA.
Roy
Soumya Sinha
SS
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Walter
Ludivine
L
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Hajnóczky
György
G
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Gross
Atan
A
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C550380:Mtch2 protein, mouse; D053218:Receptors, Death Domain