The origin of the autophagosomal membrane in human atherosclerotic plaque: a preliminary ultrastructural study

Autophagy is an evolutionarily conserved process that occurs ubiquitously and functions as a primary route for the degradation of damaged organelles and proteins in response to starvation, oxidative stress, and other harmful conditions. The initial event upon autophagy induction is the formation of a membranous cistern called the phagophore or isolation membrane, a cup-shaped structure that elongates, engulfs cytoplasmic "cargo", and fuses at its rims to give rise to the autophagosome within which cytoplasmic material is enclosed. Although thoroughly studied in diverse cell culture systems, few attempts have been made to analyze the membrane dynamics during phagophore biogenesis in tissues. With respect to the cardiovascular system, no structural information is currently available regarding the sources that may contribute to the nucleation and growth of the phagophore membrane. The results presented here demonstrate that in the cells of human atherosclerotic plaque the phagophores are in contact with the endoplasmic reticulum (ER) membranes. Initially, the phagophore appears as a membrane sac that enwraps injured organelles and dysfunctional proteins and then matures into a double-membrane, closed structure often containing portions of the ER. These structural data indicate that the membrane source that elongates the phagophore might probably come from the ER. The topographical relationship between the ER tubules and the phagophore might also favor an efficient mechanism to transfer lipids from their site of synthesis to the nascent membrane, thus promoting its elongation and, ultimately, the formation of the autophagosome.