Autolamellasomes: An Autophagy-Dependent Parallel Pathway for Bulk ER Degradation and Lysosome Biogenesis

Autophagy maintains cellular homeostasis through lysosomal degradation of cytoplasmic components, yet how prolonged autophagy activation reshapes organelle architecture remains poorly understood. Here we identify a previously unrecognized form of endoplasmic reticulum (ER) remodeling induced by chronic mTOR inhibition. We show that sustained autophagy triggers the formation of multilamellar ER-derived structures, termed autolamellasomes, which mediate bulk ER degradation. Unlike canonical ER-phagy, autolamellosome biogenesis requires the core autophagy machinery but is independent of all known ER-phagy receptors. Using cryo-electron tomography, correlative light–electron microscopy, and in vitro reconstitution, we demonstrate that autolamellasomes arise through autophagy-dependent assembly and compaction of fragmented ER membranes into concentric stacks subsequently engulfed by lysosomes. Autolamellosomes form constitutively at low levels across diverse cell types, accumulate in senescent cells and fibroblasts from Hutchinson–Gilford progeria syndrome (HGPS), and thus represent an aging-associated pathway linking sustained mTOR suppression to ER and lysosomal homeostasis. This work not only resolves the long-standing origin of intra-lysosomal membrane whorls but also establishes a cell-free system for dissecting autophagy-driven membrane remodeling, revealing a conserved degradative route coupling nutrient sensing to membrane turnover, lipid catabolism, and aging.