Schull, S., Guenther, S. D., Brodesser, S., Seeger, J. M., Tosetti, B., Wiegmann, K., Pongratz, C., Diaz, F., Witt, A., Andree, M., Brinkmann, K., Kroenke, M., Wiesner, R. J. and Kashkar, H. (2015). Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. Cell Death Dis., 6. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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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 C-16 : 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schull, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, S. D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tosetti, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiegmann, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pongratz, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andree, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkmann, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesner, R. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-410330
DOI: 10.1038/cddis.2015.62
Journal or Publication Title: Cell Death Dis.
Volume: 6
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-4889
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LONGEVITY-ASSURANCE GENE; SPHINGOLIPID METABOLISM; MOUSE MODEL; COMPLEX IV; CELL-DEATH; BAX; DISEASES; INHIBITION; MUTATION; PATHWAYMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41033

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