Autophagy: a forty-year search for a missing membrane source

Abstract

Autophagy is central to diverse biological processes in eukaryotes including animal development and cellular survival, and also to neurodegenerative diseases, but the origin of the membranes that make up autophagic vesicles is unknown.

Figure 1. The Dynamic Membrane Events Involved in Autophagy

(A) Upon induction of autophagy, a membrane sac called the isolation membrane (IM) forms and engulfs portions of the cytoplasm. Sealing of its edges gives rise to the double-membrane bound autophagosome. Fusion of the outer membrane with a lysosome results in formation of an autolysosome, in which the inner autophagosomal membrane and its contents are degraded. (B) Starvation-induced autophagosomes (AP) and autolysosomes (AL) in the fat body (the functional analogue of the liver) of a fruit fly larva. Note that APs contain intact cytoplasm, whereas the contents of ALs show various stages of degradation. (C) Liver cells of starved mice carrying a fluorescently tagged LC3 transgene, labeling cup-shaped and ring-shaped structures that correspond to IMs and autophagosomes, respectively. Images courtesy of Ryan Scott (B) and Dr. Noboru Mizushima (C).

Figure 2. Possible Membrane Sources of the IM

Some of the possible scenarios for IM formation are illustrated here. According to the maturation model, upon induction of autophagy, membrane may be directly derived from the ER by folding (A), or in the form of vesicular transport (B). In the assembly model, membrane may be assembled de novo at the site of IM formation, originating from nonvesicular transport, such as micellar, as shown in (C), or local synthesis (D). See text for further details.