The Dynamics of the ESCRT Machinery in Open Mitosis from Physiology to Pathology

Highlights: What are the main findings? In open mitosis, ESCRTs type III are recruited to the anaphase/telophase chromatin core by BAF1 and LEM2; CHMP7 and IST1 bring in VPS4 and Spastin to couple nuclear envelope reformation with spindle microtubule disassembly. Canonical ESCRTs type I and II have not yet been identified as part of this nuclear envelope ESCRT module. Beyond mitosis, the same axis operates during interphase nuclear envelope rupture and repair. ESCRT factors also contribute to nuclear pore complex quality control. What are the implication of the main findings? Correct ESCRTs type III assembly in mitosis is essential for nuclear reformation and genome integrity. ESCRT dysfunction causes DNA damage, spindle clearance defects, and chromosomal instability, mechanistically linking ESCRTs to disease including cancer and neurodegeneration. ESCRT-dependent nuclear envelope surveillance pathways are emerging as therapeutic entries. Moreover, candidate new factors, such as the ESCRT type I like factor AKTIP, suggest additional druggable nodes. The Endosomal Sorting Complex Required for Transport (ESCRT) is a highly conserved machinery best known for its role in endosomal trafficking and membrane remodeling. Increasing evidence shows that ESCRT components are also key regulators during open mitosis, where precise membrane dynamics are essential for nuclear envelope reformation and spindle disassembly. In this review, we explore how the ESCRT machinery coordinates mitotic processes under physiological conditions and how their dysregulation contributes to genomic instability, altered cell division, and disease. We highlight recent findings on the spatiotemporal control of ESCRT recruitment at mitotic membranes, the interplay with chromatin and nuclear envelope-associated factors, and the consequences of defective ESCRT function in pathological contexts such as cancer and neurodegeneration. By connecting molecular mechanisms with cellular outcomes, we provide an integrated view of how the ESCRT machinery acts as critical guardian of mitotic fidelity and offer some routes for the identification of potential therapeutic targets in human disease.