title: Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.
abstract: Mitochondrial morphology is regulated by fusion and fission machinery. Impaired mitochondria dynamics cause various diseases, including Alzheimer's disease. Appoptosin (encoded by SLC25A38) is a mitochondrial carrier protein that is located in the mitochondrial inner membrane. Appoptosin overexpression causes overproduction of reactive oxygen species (ROS) and caspase-dependent apoptosis, whereas appoptosin downregulation abolishes β-amyloid-induced mitochondrial fragmentation and neuronal death during Alzheimer's disease. Herein, we found that overexpression of appoptosin resulted in mitochondrial fragmentation in a manner independent of its carrier function, ROS production or caspase activation. Although appoptosin did not affect levels of mitochondrial outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (OPA1) and fission [DRP1 (also known as DNM1L) and FIS1] proteins, appoptosin interacted with MFN1 and MFN2, as well as with the mitochondrial ubiquitin ligase MITOL (also known as MARCH5) but not OPA1, FIS1 or DRP1. Appoptosin overexpression impaired the interaction between MFN1 and MFN2, and mitochondrial fusion. By contrast, co-expression of MFN1, MITOL and a dominant-negative form of DRP1, DRP1(K38A), partially rescued appoptosin-induced mitochondrial fragmentation and apoptosis, whereas co-expression of FIS1 aggravated appoptosin-induced apoptosis. Together, our results demonstrate that appoptosin can interact with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Cuilin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Zhun
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Guiying
authors.initials: G
authors.lastname: Liu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China Degenerative Disease Research Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, Fujian 361102, China yunzhang@xmu.edu.cn.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D053142:Mitochondrial Size; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C476525:FIS1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C553226:Slc25a38 protein, human; C515578:MARCHF5 protein, human; D044767:Ubiquitin-Protein Ligases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Apoptosis; Appoptosin; MFN1; MFN2; MITOL; Mitochondrial dynamics
references.citation: Mol Cell Biol. 2012 Jan;32(2):309-19
references.pmid: 22083962
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10190-5
references.pmid: 21646527
references.citation: Science. 2012 Aug 31;337(6098):1062-5
references.pmid: 22936770
references.citation: J Neurosci. 2012 Oct 31;32(44):15565-76
references.pmid: 23115192
references.citation: Mol Neurodegener. 2013;8:32
references.pmid: 24067127
references.citation: N Engl J Med. 2013 Dec 5;369(23):2236-51
references.pmid: 24304053
references.citation: Mol Neurodegener. 2013;8:36
references.pmid: 24148220
references.citation: Mol Neurodegener. 2014;9:6
references.pmid: 24410826
references.citation: Cell Death Dis. 2014;5:e1172
references.pmid: 24722297
references.citation: Am J Physiol Cell Physiol. 2014 Jun 15;306(12):C1176-83
references.pmid: 24740540
references.citation: Cancer Lett. 2015 Mar 1;358(1):47-58
references.pmid: 25541060
references.citation: Mol Biol Cell. 1999 Dec;10(12):4403-17
references.pmid: 10588666
references.citation: Dev Cell. 2001 Oct;1(4):515-25
references.pmid: 11703942
references.citation: J Cell Biol. 2002 Dec 23;159(6):931-8
references.pmid: 12499352
references.citation: J Cell Biol. 2003 Jan 20;160(2):189-200
references.pmid: 12527753
references.citation: J Biol Chem. 2003 Sep 19;278(38):36373-9
references.pmid: 12783892
references.citation: Biochem J. 2004 Apr 1;379(Pt 1):183-90
references.pmid: 14674884
references.citation: Science. 2004 Aug 6;305(5685):858-62
references.pmid: 15297672
references.citation: J Submicrosc Cytol. 1985 Jul;17(3):459-64
references.pmid: 2991550
references.citation: FEBS Lett. 1994 Jun 6;346(1):48-54
references.pmid: 8206158
references.citation: J Cell Biol. 1998 Feb 23;140(4):821-9
references.pmid: 9472034
references.citation: J Cell Biol. 1998 Oct 19;143(2):351-8
references.pmid: 9786947
references.citation: J Cell Sci. 2004 Dec 15;117(Pt 26):6535-46
references.pmid: 15572413
references.citation: J Biol Chem. 2005 Jul 1;280(26):25060-70
references.pmid: 15878861
references.citation: FASEB J. 2006 Jun;20(8):1275-7
references.pmid: 16645044
references.citation: EMBO J. 2006 Aug 9;25(15):3618-26
references.pmid: 16874301
references.citation: EMBO Rep. 2006 Oct;7(10):1019-22
references.pmid: 16936636
references.citation: Genomics. 2006 Dec;88(6):779-90
references.pmid: 16949250
references.citation: J Cell Biol. 2007 Feb 12;176(4):405-14
references.pmid: 17296794
references.citation: Cell Death Differ. 2007 Apr;14(4):651-61
references.pmid: 17218957
references.citation: J Biol Chem. 2007 Apr 13;282(15):11521-9
references.pmid: 17301055
references.citation: J Cell Biol. 2007 Jul 2;178(1):71-84
references.pmid: 17606867
references.citation: J Biol Chem. 2007 Jul 27;282(30):21583-7
references.pmid: 17553808
references.citation: J Biol Chem. 2007 Aug 10;282(32):23354-61
references.pmid: 17562700
references.citation: EMBO Rep. 2007 Oct;8(10):939-44
references.pmid: 17721437
references.citation: Circ Res. 2007 Nov 26;101(11):1113-22
references.pmid: 17901359
references.citation: Nat Rev Neurosci. 2008 Jul;9(7):505-18
references.pmid: 18568013
references.citation: Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):860-6
references.pmid: 18515060
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
references.pmid: 19050078
references.citation: Science. 2009 Apr 3;324(5923):102-5
references.pmid: 19342591
references.citation: Nat Genet. 2009 Jun;41(6):651-3
references.pmid: 19412178
references.citation: Physiol Rev. 2009 Jul;89(3):799-845
references.pmid: 19584314
references.citation: J Neurosci. 2009 Jul 15;29(28):9090-103
references.pmid: 19605646
references.citation: J Alzheimers Dis. 2010;20 Suppl 2:S609-31
references.pmid: 20463406
references.citation: Nat Rev Mol Cell Biol. 2010 Dec;11(12):872-84
references.pmid: 21102612
references.citation: Mol Cell Biol. 2011 Mar;31(6):1309-28
references.pmid: 21245373
references.citation: FEBS J. 2011 Apr;278(6):941-54
references.pmid: 21232014
references.citation: PLoS Biol. 2011 Apr;9(4):e1000612
references.pmid: 21526220
references.citation: Haematologica. 2011 Jun;96(6):808-13
references.pmid: 21393332
references.citation: Hum Mol Genet. 2011 Jul 1;20(13):2495-509
references.pmid: 21459773
references.citation: FASEB J. 2012 May;26(5):2175-86
references.pmid: 22321727