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Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration
Journal article   Peer reviewed

Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration

Breanne R Hewitt, Jacob J Duggan and Ryan J Petrie
Molecular biology of the cell, v 37(10), par100
02 Sep 2026
DOI: https://doi.org/10.1091/mbc.E26-06-0250
PMID: 42684849

Abstract

Cell Movement - physiology Cell Nucleus - metabolism Cells, Cultured Extracellular Matrix - metabolism Extracellular Matrix - physiology Fibroblasts - metabolism Fibroblasts - physiology Humans Mitochondria - metabolism Mitochondria - physiology Mitochondrial Dynamics - physiology rho-Associated Kinases - metabolism Vimentin - metabolism
Cells migrating through three-dimensional (3D) tissues adapt their mechanical properties in response to extracellular matrix architecture through migratory plasticity. In primary human dermal fibroblasts, matrix elasticity drives distinct low- and high-pressure migration modes in which forces either push or pull the nucleus, respectively. How these mechanically distinct modes of nuclear translocation influence mitochondrial organization and function is not known. Here, we show that mitochondria become enriched anterior to the nucleus during 3D migration and segregate into spatially distinct populations with different motility and energetic states. During high-pressure, nuclear-pulling migration, a highly energized mitochondrial pool forms immediately anterior to the nucleus. This mitochondrial pool occupies a specialized perinuclear compartment organized by ROCK-dependent contractility and vimentin intermediate filaments and is selectively lost when this machinery is disrupted. Together, these findings reveal that extracellular matrix mechanics spatially organize mitochondrial dynamics and energetics during 3D migration, coupling localized mitochondrial function to the mechanical requirements of nuclear translocation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

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