{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:22:39Z","timestamp":1793276559339,"version":"4.5.0"},"reference-count":63,"publisher":"American Society for Cell Biology (ASCB)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:p>Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive \u201cbeads-on-a-string\u201d morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of \u201cpearls\u201d connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here, we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes, for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T-cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling: 1) ionic flux producing internal osmotic pressure, 2) membrane packing lowering bending elasticity, and 3) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.<\/jats:p>","DOI":"10.1091\/mbc.e25-06-0302","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:24:03Z","timestamp":1759940643000},"source":"Crossref","is-referenced-by-count":12,"title":["The biophysical mechanism of mitochondrial pearling"],"prefix":"10.1091","volume":"36","author":[{"given":"Gabriel","family":"Sturm","sequence":"first","affiliation":[{"name":"University of California, San Francisco, San Francisco, CA 94158"},{"name":"Calico Life Sciences LLC, South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayley","family":"Hake","sequence":"additional","affiliation":[{"name":"Calico Life Sciences LLC, South San Francisco, CA 94080"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin 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