Mitochondrial-Derived Vesicles Mediate Interorganellar Communication via Selective Cargo Transfer Under Oxidative Stress

Mitochondrial-derived vesicles (MDVs) are essential for mitochondrial quality control, yet their cargo specificity and role in interorganellar communication remain poorly characterized. Here, we demonstrate that under oxidative stress, MDVs selectively transport antioxidant enzymes (e.g., peroxiredoxin-3, SOD1) to peroxisomes and lysosomes via Rab32-dependent trafficking. Using super-resolution microscopy and SILAC-based proteomics in HeLa and primary murine fibroblast models, we observed a 3-fold increase in MDV biogenesis post-H ₂ O treatment ( p  < 0.001), with Rab32 knockout cells exhibiting 50% higher cytosolic mitochondrial DNA (mtDNA) leakage and NLRP3 inflammasome activation. Live-cell imaging confirmed MDV-peroxisome fusion via PEX14 and lysosomal delivery via LAMP1, revealing a redox-sensitive mechanism that prevents oxidative damage. These findings establish MDVs as critical mediators of interorganellar coordination, offering novel therapeutic strategies for diseases linked to mitochondrial dysfunction, such as Parkinson’s disease.