Hamed, M.; Gao, Y.; Stein, F.; Vijay, G.; Stausberg, T.; Juehlen, R.; Martin, I. V.; Raffetseder, U.; Stamellou, E.; Kramann, R.; Ostendorf, T.; Antonin, W.

The nuclear envelope, with its nuclear pore complexes, establishes a selective barrier that maintains the spatial organization of the cellular proteome. Whether this barrier remains intact in long-lived postmitotic cells during aging is largely unknown. Here, we show that aging podocytes experience a progressive loss of nuclear-cytoplasmic compartmentalization. Using subcellular proteomics and quantitative imaging, we identify a global redistribution of proteins between the nucleus and cytoplasm, affecting key regulators of RNA processing, chromatin organization, and cellular metabolism. Loss of compartmentalization is accompanied by mitochondrial dysfunction, increased reactive oxygen species production, and aberrant nuclear accumulation of YAP1, linking nuclear barrier failure to metabolic and transcriptional dysregulation. These findings identify nuclear envelope dysfunction as a driver of proteome disorganization and cellular decline in aging podocytes and suggest that loss of nuclear-cytoplasmic compartmentalization represents a general mechanism contributing to dysfunction in long-lived cells.