JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunctionстатья
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Дата последнего поиска статьи во внешних источниках: 30 января 2024 г.
Аннотация:A cardinal feature of brain tissue injury in stroke is mitochon-
drial dysfunction leading to cell death, yet remarkably little is
known about the mechanisms underlying mitochondrial injury
in cerebral ischemia/reperfusion (IR). Ceramide, a naturally
occurring membrane sphingolipid, functions as an important
second messenger in apoptosis signaling and is generated by de
novo synthesis, sphingomyelin hydrolysis, or recycling of sphin-
golipids. In this study, cerebral IR-induced ceramide elevation
resulted from ceramide biosynthesis rather than from hydroly-
sis of sphingomyelin. Investigation of intracellular sites of cera-
mide accumulation revealed the elevation of ceramide in mito-
chondria because of activation of mitochondrial ceramide
synthase via post-translational mechanisms. Furthermore, cer-
amide accumulation appears to cause mitochondrial respiratory
chain damage that could be mimicked by exogenously added
natural ceramide to mitochondria. The effect of ceramide on
mitochondria was somewhat specific; dihydroceramide, a struc-
ture closely related to ceramide, did not inflict damage. Stimu-
lation of ceramide biosynthesis seems to be under control of
JNK3 signaling: IR-induced ceramide generation and respira-
tory chain damage was abolished in mitochondria of JNK3-de-
ficient mice, which exhibited reduced infarct volume after IR.
These studies suggest that the hallmark of mitochondrial injury
in cerebral IR, respiratory chain dysfunction, is caused by the
accumulation of ceramide via stimulation of ceramide synthase
activity in mitochondria, and that JNK3 has a pivotal role in
regulation of ceramide biosynthesis in cerebral IR.