title: Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3) has a key role in the mitochondrial dysfunction induced by mutant huntingtin.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG repeat in the IT15 gene that encodes the protein huntingtin (htt). Evidence shows that mutant htt causes mitochondrial depolarization and fragmentation, but the underlying molecular mechanism has yet to be clarified. Bax/Bak and BNip3 are pro-apoptotic members of the Bcl-2 family protein whose activation triggers mitochondrial depolarization and fragmentation inducing cell death. Evidence suggests that Bax/Bak and BNip3 undergo activation upon mutant htt expression but whether these proteins are required for mitochondrial depolarization and fragmentation induced by mutant htt is unclear. Our results show that BNip3 knock-out cells are protected from mitochondrial damage and cell death induced by mutant htt whereas Bax/Bak knock-out cells are not. Moreover, deletion of BNip3 C-terminal transmembrane domain, required for mitochondrial targeting, suppresses mitochondrial depolarization and fragmentation in a cell culture model of HD. Hence, our results suggest that changes in mitochondrial morphology and transmembrane potential, induced by mutant htt protein, are dependent and linked to BNip3 and not to Bax/Bak activation. These results provide new compelling evidence that underlies the molecular mechanisms by which mutant htt causes mitochondrial dysfunction and cell death, suggesting BNip3 as a potential target for HD therapy.
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sassone
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Victoria
authors.initials: V
authors.lastname: Margulets
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
authors.forename: AnnaMaria
authors.initials: A
authors.lastname: Maraschi
authors.affiliation: Fondazione Filarete, viale Ortles 22/4, 20139 Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rodighiero
authors.affiliation: Department of BIOMETRA, CNR Institute of Neuroscience, University of Milan, 20129 Milan, Italy and.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy, Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciammola
authors.affiliation: Department of Physiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada, jenny.sassone@istituto-besta.it jennysassone@hotmail.com Lorrie@sbrc.ca.
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy, jenny.sassone@istituto-besta.it jennysassone@hotmail.com Lorrie@sbrc.ca.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sassone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C090121:BNIP3 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein