The endoplasmic reticulum (ER) is a major organelle for calcium storage and transport. In cortical neurons, spontaneous periodic calcium bursts are critical for cell development and signaling. Experiments show that disrupting ER morphology—from a tubular network to a partially fragmented, vesicular structure—abolishes these oscillations, despite preserved ER Ca 2+ storage and release capability. We use physical modeling to address the mechanistic connection between ER architecture and its ability to support Ca 2+ bursting. Specifically, we model the ER as a 3D spatial network to quantify how its structure affects Ca 2+ refill via store-operated entry at ER-plasma membrane contact sites. Our calculations reveal that ER fragmentation slows global refill, as ions must traverse narrow connections between voluminous vesicular traps. We link the hindered refill rate to reduced oscillatory activity through a nonlinear aspatial model for Ca 2+ exchange between the ER, cytoplasm, and extracellular space. Using refill rates estimated from 3D simulations, the model reproduces key experimental trends: sustained Ca 2+ oscillation with wild-type ER, and damped Ca 2+ oscillation when refill is impaired by ER fragmentation. Thus, transport through a well-connected ER morphology is critical for efficient Ca 2+ refill, underpinning the ER’s ability to support neuronal bursts. We further explore effects of ER structure on other transport problems, including the self-assembly of organelle contact sites on the ER. Reaction-diffusion models of mobile tethers on a tubular network are used to investigate how connectivity modulates contact site lifetimes and dynamic response. Notably, morphogens shaping ER structure are associated with neurodegenerative diseases. By demonstrating how perturbations to ER structure disrupt calcium bursts and contact site formation, our model provides a possible explanation for how morphology changes drive functional breakdown in neurons and why these cells may be especially vulnerable in disease.
Zhang et al. (Sun,) studied this question.