Brefeldin A (BFA), an endoplasmic reticulum (ER)-Golgi transport inhibitor, has been shown to cause accumulation of proteins in the ER, ER stress, and ultimately apoptosis. In this paper, we demonstrate that the knockdown of mitochondrial NAD(+)-dependent isocitrate dehydrogenase (IDPm), a mitochondrial NADPH-generating enzyme, by small interfering RNA (siRNA) enhanced BFA-induced apoptosis. However, attenuated IDPm activity results in the suppression of ER stress response, presumably, via the inhibition of the PI3K/Akt pathway. Collectively, our data suggest that the association of IDPm expression and ER stress confers a survival mechanism in A549 cells against BFA-induced apoptosis. (C) 2011 Elsevier Inc. All rights reserved.