Mitochondrial pearling: membrane biophysics, Ca2+-dependent regulation, mtDNA nucleoid dynamics, and emerging links to mitochondrial quality control and neurological disorders

Abstract

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.