title: Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.
abstract: Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches. The elevated CerS6 activity resulted in accumulation of the pro-apoptotic C16 : 0 ceramide, which facilitates the mitochondrial apoptosis in response to oxidative stress. Accordingly, inhibition of CerS6 or its specific knockdown diminished the increased susceptibility of COX-deficient cells to oxidative stress. Our results provide new insights into how mitochondrial RC dysfunction mechanistically interferes with the apoptotic machinery. On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction.
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schüll
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: S D
authors.initials: SD
authors.lastname: Günther
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Seeger
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Tosetti
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Wiegmann
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Pongratz
authors.affiliation: Department of Neurology, University of Miami, Miami, FL, USA.
authors.forename: F
authors.initials: F
authors.lastname: Diaz
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Witt
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Andree
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Brinkmann
authors.affiliation: 1] Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krönke
authors.affiliation: 1] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Cologne, Germany [2] Institute for Vegetative Physiology, University of Cologne, Cologne, Germany.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wiesner
authors.affiliation: 1] Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003576:Electron Transport Complex IV / Q000096:biosynthesis* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010101:Oxygen Consumption; D051049:Sphingosine N-Acyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D008565:Membrane Proteins; D003576:Electron Transport Complex IV; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase