Ca²⁺-induced lysosomal dysfunction promotes SR-derived vesicle accumulation and microtubule aster formation in PLN R14del cardiomyopathy

Furthermore, we show that these SR-derived vesicle-like structures often localize adjacent to lysosomes. Interestingly, Ca²⁺dysregulation in plna R14del hearts leads to reduced lysosomal function, resulting in the accumulation of SR-derived vesicle-like structures at the microtubule organizing center (MTOC). Strikingly, the accumulation of vesicle-like structures at the MTOC is accompanied by reorganization of the linear microtubule network into asters, ion-channel mislocalization, sarcomere disorganization, and nuclear deformation.

Restoration of lysosomal function through Ca²⁺ buffering or fasting reduces vesicle accumulation, restores microtubule organization, and rescues cellular architecture. Collectively, our study defines a Ca²⁺-sensitive pathway linking the formation of SR-derived vesicle-like structures, lysosomal dysfunction, and microtubule remodeling to pathological cellular rearrangements.