Investigating the subcellular distribution and protein interaction of APOE and the modulation by cellular stress signals, we aimed to contribute to the elucidation of putative novel functions. We identified APOE as hepatic mitochondria-associated ER-membranes (MAM) protein, where it most likely interacts with the mitochondrial proteins LONP1, TOMM40 and VDAC1. We pro-pose that the interaction with TOMM40 and VDAC1 enables specific mitochondria-ER contacts with so far unknown functional relevance. However, MAM residing APOE may help in unfolded protein response possibly by co-operation with LONP1 at the interface of mitochondria and ER membranes.