Presenilins are mutated in most cases of autosomal dominant inherited forms of early onset Alzheimer's disease and such mutations are known to sensitize cells to apoptotic stimuli in vitro. Previous studies show that presenilins are primarily located in the endoplasmatic reticulum and cell membranes. Here we report, based on immunoblot analysis and immunoelectron microscopy studies, that PSI is also located in mitochondrial membranes. For these studies we used tissue sections and subcellular fractions of rat brain and liver. Immunogold labeling of sections show that PSI is predominantly located in the inner membrane of mitochondria. The function of PSI in mitochondrial membranes is presently unknown. PSI mutations may make cells more vulnerable to apoptotic Stimuli due to dysfunction of this protein at the mitochondrial level. (C) 2002 Elsevier Science (USA). All rights reserved.