The lipid and receptor-binding regions act in concert to cause mitochondrial mislocalization of apoE4 fragments. Cells transfected with WT apoE4 (a), apoE(171-272) (c), apoE4(1-240) (e), apoE4(1-272)-AARA with four mutations (I250A, F257A, W264R, and V269A) in the lipid-binding region (g), or apoE4(1-272)-3A with three mutations (R142A, K146A, and R147A) in the receptor-binding region (i) were permeabilized with 0.5% Tween 20 (a, c, e, g, and i) and stained with anti-apoE (green). Cells cotransfected with DsRed2-Mito (red) and various apoE4 constructs mentioned above were permeabilized with 500 units of STP-O (b, d, f, h, and j) and stained with anti-apoE (green). The cells were then analyzed by confocal microscopy for only green (a, c, e, g, and i) or both red and green (b, d, f, h, and j).