Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.

Download
Author
Schüll, S; Günther, SD; Brodesser, S; Seeger, JM; Tosetti, B; Wiegmann, K; Pongratz, C; Diaz, F; Witt, A; Andree, M; ...Date
2015-03-12Source Title
Cell Death and DiseasePublisher
Springer Science and Business Media LLCUniversity of Melbourne Author/s
Brinkmann, KerstinAffiliation
Medical Biology (W.E.H.I.)Metadata
Show full item recordDocument Type
Journal ArticleCitations
Schüll, S., Günther, S. D., Brodesser, S., Seeger, J. M., Tosetti, B., Wiegmann, K., Pongratz, C., Diaz, F., Witt, A., Andree, M., Brinkmann, K., Krönke, M., Wiesner, R. J. & Kashkar, H. (2015). Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.. Cell Death Dis, 6 (3), pp.e1691-. https://doi.org/10.1038/cddis.2015.62.Access Status
Open AccessOpen Access at PMC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385940Abstract
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.
Export Reference in RIS Format
Endnote
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
Refworks
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References