Beyond Autophagy: VPS39 Deficiency Triggers Migrasome-Driven Stress Adaptation Revealed by Super-Resolution Imaging

Abstract: Autophagy and migrasome formation constitute critical cellular mechanisms for maintaining cellular homeostasis, however, their potential compensatory interplay remains poorly understood. In this study, we identify VPS39, a core component of the HOPS complex, as a molecular switch coordinating these processes. Genetic ablation of VPS39 not only impairs autophagic flux but also triggers cell migration through RhoA/Rac1 GTPases upregulation, consequently facilitating migrasome formation. Using super-resolution microscopy, we further demonstrate that migrasomes serve as an alternative disposal route for damaged mitochondria during VPS39-induced autophagy impairment, revealing a novel stress adaptation mechanism. Our work establishes a previously unrecognized autophagy-migrasome axis and provides direct visual evidence of organelle quality control via migrasomal extrusion. These findings position VPS39-regulated pathway switching as a potential therapeutic strategy for neurodegenerative diseases characterized by autophagy dysfunction.