Spatial regulation of mitochondrial membrane potential by α5β1 integrin engagement in collective cell migration

This study reveals a mechanistic connection between extracellular matrix (ECM) engagement, integrin signaling, and mitochondrial bioenergetic regulation during collective cell migration. Using *Xenopus laevis* mesendoderm tissues as a developmental model, the authors show that mitochondrial membrane potential (MMP) is spatially elevated at the leading edge of migrating cell cohorts where α5β1 integrin–fibronectin traction forces are highest. Real-time metabolic analysis demonstrates that α5β1 engagement enhances respiratory efficiency, and this effect is diminished by inhibition of focal adhesion kinase (FAK) signaling. Engagement of both the RGD and PPSRN synergy sites of fibronectin is required to elicit maximal increases in MMP. Mechanical stretching of cells on deformable fibronectin substrates produces a FAK-dependent increase in mitochondrial activity, linking substrate mechanics to cellular metabolism. In vivo experiments further demonstrate that disrupting MMP or ATP synthase slows collective cell migration, highlighting bioenergetics as a functional contributor to tissue-scale morphogenesis.