Mitochondrial pearling: membrane biophysics, Ca²⁺-dependent regulation, mtDNA nucleoid dynamics, and emerging links...

Mitochondrial dynamics has long been interpreted primarily through fission and fusion, yet tubular mitochondria can also undergo rapid pearling, a phenomenon in which elongated mitochondria reorganize into a beads-on-a-string morphology while retaining a continuous imaged contour. The occurrence and biological relevance of mitochondrial pearling require careful study. The dimensionless tension-bending ratio used to organize these observations is a heuristic analogy to single-membrane tubes, not a validated quantitative model of the mitochondrial double membrane. Evidence does not yet establish a continuous sequence from pearling through coordinated outer- and inner-membrane scission to mitophagy or intercellular mitochondrial transfer; those links are therefore presented as hypotheses and testable predictions. We use the provisional term "candidate disease-associated sustained pearling phenotype" only for within-study events that meet dynamic pearling criteria and show longer duration or delayed/failed reversal relative to appropriately matched controls. No universal duration threshold or validated pearling-defined disease entity currently exists. Event duration, wavelength, un-pearling kinetics, separate outer- and inner-membrane continuity, and the fate of individual pearls should be measured together to determine whether sustained events are incidental, adaptive, or causally involved in disease.