Spatial organization of mitochondria in 3D cell migration

Breanne R. Hewitt

doi:10.17918/00011534

Cell migration is a fundamental biological process required for embryonic development, tissue repair, immune surveillance, and cancer metastasis. To successfully navigate the diverse mechanical environments encountered in vivo, cells exhibit migratory plasticity, the ability to dynamically alter their migration strategy in response to extracellular matrix architecture and mechanics. Distinct migration modes employ unique force-generating mechanisms that require extensive reorganization of the cytoskeleton, intracellular architecture, and cellular energetics. Understanding how cells coordinate these adaptations remains a central question in cell biology. The first chapter provides the conceptual framework for this work by reviewing the mechanisms that govern cell migration in three-dimensional (3D) environments. Particular emphasis is placed on migratory plasticity, the ability of cells to transition between distinct migration strategies in response to extracellular matrix architecture and mechanics. This chapter discusses how changes in cell-ECM adhesion, actomyosin contractility, intracellular pressure, and cytoskeletal organization enable cells to navigate diverse tissue environments. It also examines the emerging role of mitochondria in cell migration, highlighting how mitochondrial positioning and function are coordinated with localized energetic demands and identifying important gaps in our understanding of how mitochondrial organization is regulated during 3D migration. The second chapter explores how these distinct mechanical programs influence mitochondrial organization. Because mitochondria are dynamically positioned to meet localized energetic demands, I investigated mitochondrial distribution, dynamics, and membrane potential during fibroblast migration through mechanically distinct 3D environments. Using cell-derived matrices (CDMs), which promote nuclear piston migration, and collagen I matrices, which support lamellipodial migration, I demonstrate that matrix mechanics drive the formation of spatially distinct mitochondrial populations with unique organizational and functional properties. During nuclear piston migration, mitochondria become enriched within a specialized anterior perinuclear compartment characterized by elevated membrane potential and reduced organelle motility. Disruption of the contractile machinery responsible for nuclear pulling abolishes this anterior energetic compartment, demonstrating that matrix mechanics coordinate mitochondrial organization with the force-generating mechanisms of migration. Finally, this dissertation investigates the cytoskeletal architecture responsible for transmitting force during nuclear piston migration. While previous work established that vimentin intermediate filaments connect the nucleus to the cytoskeleton through Nesprin-3, this work identifies plectin as the mechanosensitive cytolinker that couples vimentin intermediate filaments to the actomyosin cytoskeleton. These findings establish the molecular linkage that enables actomyosin-generated forces to be transmitted to the nucleus during pressure-driven migration and provide a mechanistic framework for understanding nuclear force transmission in confined 3D environments. Together, this work demonstrates that extracellular matrix mechanics regulate both the mechanical and energetic organization of migrating cells through migratory plasticity. By integrating cytoskeletal force transmission with mitochondrial compartmentalization, these studies provide new insight into how cells coordinate intracellular architecture to support efficient migration through complex three-dimensional tissues.

Spatial organization of mitochondria in 3D cell migration

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Spatial organization of mitochondria in 3D cell migration

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