title: CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation.
abstract: Mitochondrial outer membrane permeabilization (MOMP) is a critical control point during apoptosis that results in the release of pro-apoptotic mitochondrial contents such as cytochrome c. MOMP is largely controlled by Bcl-2 family proteins such as Bax, which under various apoptotic stresses becomes activated and oligomerizes on the outer mitochondrial membrane. Bax oligomerization helps promote the diffusion of the mitochondrial contents into the cytoplasm activating the caspase cascade. In turn, Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL, which was recently shown to prevent Bax from accumulating at the mitochondria. However, the exact mechanisms by which Bcl-xL regulates Bax and thereby MOMP remain partially understood. In this study, we show that the small CHCH-domain-containing protein CHCHD2 binds to Bcl-xL and inhibits the mitochondrial accumulation and oligomerization of Bax. Our data show that in response to apoptotic stimuli, mitochondrial CHCHD2 decreases prior to MOMP. Furthermore, when CHCHD2 is absent from the mitochondria, the ability of Bcl-xL to inhibit Bax activation and to prevent apoptosis is attenuated, which results in increases in Bax oligomerization, MOMP and apoptosis. Collectively, our findings establish CHCHD2, a previously uncharacterized small mitochondrial protein with no known homology to the Bcl-2 family, as one of the negative regulators of mitochondria-mediated apoptosis.
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Curriculum in Genetics and Molecular Biology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: H V
authors.initials: HV
authors.lastname: Clegg
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Curriculum in Genetics and Molecular Biology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Leslie
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Di
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Curriculum in Genetics and Molecular Biology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Tollini
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Curriculum in Genetics and Molecular Biology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: T-H
authors.initials: TH
authors.lastname: Kim
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Graves
authors.affiliation: Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: 1] Department of Radiation Oncology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Lineberger Comprehensive Cancer Center, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, China [4] Department of Pharmacology, School of Medicine University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C580880:CHCHD2 protein, human; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein