A phosphoinositide switch from PI(4,5)P ₂ to PI4P triggers endocytosis by inducing dynamin-mediated fission in secretory cells

Endocytosis generates life-essential vesicles via complex protein-lipid machinery, yet its initiation mechanisms remain elusive. Long thought to require full machinery spatiotemporal coordination to drive the flat-to-round vesicle transformations, we reveal a notably simple initiation mechanism in neuroendocrine chromaffin cells involving only the final step, the pore closure. During calcium-triggered exocytosis, calcium activates the phosphatase synaptojanin, rapidly converting PI(4,5)P₂ to PI4P. Elevated PI4P drives the fission enzyme dynamin to close the pores of preexisting and exocytosis-generated Ω-profiles, which are sufficient to generate slow, fast, ultrafast, overshoot, and bulk endocytosis, and kiss-and-run (fusion pore closure). These findings resolve the long-standing mystery of endocytosis and fission initiation and reveal PI4P, not the widely assumed PI(4,5)P₂, as the key lipid for dynamin-mediated fission. This pathway is clinically important, as it is impaired by synaptojanin mutations associated with Parkinson's disease and seizures, and is likely disrupted in other disorders involving PI4P or PI(4,5)P₂ dysregulation.