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

S. Schüll, S. D. Günther, S. Brodesser, J. M. Seeger, B. Tosetti, K. Wiegmann, C. Pongratz, Francisca Diaz, A. Witt, M. Andree, K. Brinkmann, M. Krönke, R. J. Wiesner, H. Kashkar

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)e1691
JournalCell Death and Disease
Volume6
DOIs
StatePublished - 2015

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Cytochrome-c Oxidase Deficiency
Oxidoreductases
Apoptosis
Mitochondrial Diseases
Oxidative Stress
Electron Transport
Cell Death
Electron Transport Complex IV
N-(alpha-hydroxyoctadecanoyl)phytosphingosine
dihydroceramide desaturase

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schüll, S., Günther, S. D., Brodesser, S., Seeger, J. M., Tosetti, B., Wiegmann, K., ... Kashkar, H. (2015). Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. Cell Death and Disease, 6, e1691. https://doi.org/10.1038/cddis.2015.62

Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. / Schüll, S.; Günther, S. D.; Brodesser, S.; Seeger, J. M.; Tosetti, B.; Wiegmann, K.; Pongratz, C.; Diaz, Francisca; Witt, A.; Andree, M.; Brinkmann, K.; Krönke, M.; Wiesner, R. J.; Kashkar, H.

In: Cell Death and Disease, Vol. 6, 2015, p. e1691.

Research output: Contribution to journalArticle

Schüll, S, Günther, SD, Brodesser, S, Seeger, JM, Tosetti, B, Wiegmann, K, Pongratz, C, Diaz, F, Witt, A, Andree, M, Brinkmann, K, Krönke, M, Wiesner, RJ & Kashkar, H 2015, 'Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6', Cell Death and Disease, vol. 6, pp. e1691. https://doi.org/10.1038/cddis.2015.62
Schüll, S. ; Günther, S. D. ; Brodesser, S. ; Seeger, J. M. ; Tosetti, B. ; Wiegmann, K. ; Pongratz, C. ; Diaz, Francisca ; Witt, A. ; Andree, M. ; Brinkmann, K. ; Krönke, M. ; Wiesner, R. J. ; Kashkar, H. / Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. In: Cell Death and Disease. 2015 ; Vol. 6. pp. e1691.
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AU - Kashkar, H.

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