Ti. Gudz et al., DIRECT INHIBITION OF MITOCHONDRIAL RESPIRATORY-CHAIN COMPLEX-III BY CELL-PERMEABLE CERAMIDE, The Journal of biological chemistry, 272(39), 1997, pp. 24154-24158
Ceramide is a lipid second messenger that mediates the effects of tumo
r necrosis factor a! and other agents on cell growth and differentiati
on, Ceramide is believed to act via activation of protein phosphatase,
proline-directed protein kinase, or protein kinase C, Tumor necrosis
factor alpha-induced common pathway of apoptosis is associated with am
early impairment of mitochondria. Herein, we demonstrate that ceramid
e earn directly inhibit mitochondrial respiratory chain function, In i
solated mitochondria, a rapid decline of mitochondrial oxidative phosp
horylation occurs in the presence of N-acetylsphingosine (C-2-ceramide
), a synthetic cell-permeable ceramide analog. An investigation of the
Bite of ceramide action revealed that tbe activity of respiratory cha
in complex III is reduced by C-2-ceramide with half-maximum effect al
5-7 PM. in contrast, N-acetylsphinganine (C-2-dihydroceramide), which
lacks a functionally critical double bond and is ineffective in cells,
did not alter mitochondrial respiration or complex III activity. We s
uggest that these in vitro observations may set the stage for identify
ing a novel mechanism of regulation of mitochondrial function in vivo.