![]() In particular, our understanding of the dynamic regulation of their molecular components and substructure is lacking. As a result, biochemistry-based approaches often suffer from averaging artefacts, and most existing labelling technologies are perturbative to ERMCS size, structure and regulation (see Supplementary Text, sections 1 and 2 for discussion) 7. ![]() Nevertheless, technical limitations have limited our understanding of many aspects of ERMCS biology, as the structures are exquisitely sensitive to fixation artefacts and show remarkable biological heterogeneity even in single cells. Commonly referred to as ER–mitochondria contact sites (ERMCSs) or mitochondria–ER contact sites (MERCs), these structures are ubiquitous in eukaryotes and may exist in several distinct forms (see Supplementary Text, sections 2a–b for full discussion) 3, 4, 6, 12. This interface has been implicated in a multitude of biological processes in both health and disease, ranging from lipid synthesis and catabolism to calcium signalling and facilitation of cellular respiration 2, 3, 11. The most prevalent sites of contact between organelles in mammalian cells are between the endoplasmic reticulum (ER) and mitochondria 9, 10. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis. ![]() An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation 7, 8, a clear understanding of their nanoscale organization and regulation is still lacking. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle 5, 6. Endoplasmic reticulum–mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites 3, 4. To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle–organelle contact sites 1, 2.
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