Mitochondria Supply Membranes for Autophagosome Biogenesis during Starvation

SummaryStarvation-induced autophagosomes engulf cytosol and/or organelles and deliver them to lysosomes for degradation, thereby resupplying depleted nutrients. Despite advances in understanding the molecular basis of this process, the membrane origin of autophagosomes remains unclear. Here, we demonstrate that, in starved cells, the outer membrane of mitochondria participates in autophagosome biogenesis. The early autophagosomal marker, Atg5, transiently localizes to punctae on mitochondria, followed by the late autophagosomal marker, LC3. The tail-anchor of an outer mitochondrial membrane protein also labels autophagosomes and is sufficient to deliver another outer mitochondrial membrane protein, Fis1, to autophagosomes. The fluorescent lipid NBD-PS (converted to NBD-phosphotidylethanolamine in mitochondria) transfers from mitochondria to autophagosomes. Photobleaching reveals membranes of mitochondria and autophagosomes are transiently shared. Disruption of mitochondria/ER connections by mitofusin2 depletion dramatically impairs starvation-induced autophagy. Mitochondria thus play a central role in starvation-induced autophagy, contributing membrane to autophagosomes.

Graphical AbstractFigure optionsDownload high-quality image (422 K)Download as PowerPoint slideHighlights
► Autophagosomes are derived from mitochondrial outer membrane during starvation
► Lipids, but not most proteins, are transferred from mitochondria to autophagosomes
► Mitochondria-ER connections are required to form autophagosomes during starvation
► Mitochondrial contribution to autophagosome assembly is unique to starvation