TABLE 2.

Evidence base, claim status, and validation sequence for the core propositions.

Core proposition	Current evidence level	Principal gap	Next experiment
Ca2+ can trigger rapid, reversible mitochondrial pearling	A (direct dynamic evidence in selected systems)	Generality across cell types, Ca2+ loads, and cristae states remains unresolved	Simultaneously measure matrix Ca2+, membrane potential, λp, τp, and un-pearling rate while manipulating MCU, NCLX, and mPTP
Rapid pearling can redistribute mtDNA nucleoids and influence spacing in directly imaged models	A (model-specific direct evidence)	Existing evidence is concentrated in specific models; validation is needed in neurons and patient-derived cells	Track retention of nucleoid positions after individual pearling events during OPA1, ATAD3A, or MICOS manipulation and in patient-derived cells
Pearling may create geometry that precedes scission-dependent mitophagy	C for adjacent mitophagy mechanisms; D for the pearling link	No same-mitochondrion sequence from pearling through scission, PINK1/Parkin or receptor recruitment, engulfment, and lysosomal delivery has been demonstrated	Continuously image morphology, OMM/IMM continuity, membrane potential, scission, PINK1/Parkin or receptor recruitment, LC3, and lysosomal delivery on the same mitochondrial segment
After coordinated OMM/IMM scission, a pearl could hypothetically become a unit for TNT or large-carrier transfer	C for adjacent transfer mechanisms; D for the pearling link	No continuous pearling→neck scission→carrier loading→recipient uptake sequence has been recorded; scale matching is insufficient	In MSC–epithelial, astrocyte–neuron, and tumor–immune cocultures, continuously track pearl-neck scission, double-membrane integrity, entry of units into TNTs or large mitochondria-containing vesicles, and arrival in recipient cells
A candidate disease-associated sustained pearling phenotype may exist in selected neurological models	B/C; no disease model currently satisfies the full dynamic criteria	No validated absolute τp threshold exists, and most disease evidence is static or mechanistically adjacent	Use within-study matched controls and prespecified event-level criteria before testing causality or generalizing across diseases