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.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
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 Hdoi
10.1038/cddis.2015.62subject
Has Abstractpub_date
2015-03-12 00:00:00pages
e1691issn
2041-4889pii
cddis201562journal_volume
6pub_type
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