Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration

Author:

Schuler Max-Hinderk1,Lewandowska Agnieszka1,Caprio Giuseppe Di23,Skillern Wesley23,Upadhyayula Srigokul23,Kirchhausen Tom234,Shaw Janet M.1,Cunniff Brian23

Affiliation:

1. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112

2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115

3. Department of Cell Biology, Harvard Medical School, Boston, MA 02115

4. Department of Pediatrics, Harvard Medical School, Boston, MA 02115

Abstract

It has long been postulated, although never directly demonstrated, that mitochondria are strategically positioned in the cytoplasm to meet local requirements for energy production. Here we show that positioning of mitochondria in mouse embryonic fibroblasts (MEFs) determines the shape of intracellular energy gradients in living cells. Specifically, the ratio of ATP to ADP was highest at perinuclear areas of dense mitochondria and gradually decreased as more-peripheral sites were approached. Furthermore, the majority of mitochondria were positioned at the ventral surface of the cell, correlating with high ATP:ADP ratios close to the ventral membrane, which rapidly decreased toward the dorsal surface. We used cells deficient for the mitochondrial Rho-GTPase 1 (Miro1), an essential mediator of microtubule-based mitochondrial motility, to study how changes in mitochondrial positioning affect cytoplasmic energy distribution and cell migration, an energy-expensive process. The mitochondrial network in Miro1−/− MEFs was restricted to the perinuclear area, with few mitochondria present at the cell periphery. This change in mitochondrial distribution dramatically reduced the ratio of ATP to ADP at the cell cortex and disrupted events essential for cell movement, including actin dynamics, lamellipodia protrusion, and membrane ruffling. Cell adhesion status was also affected by changes in mitochondrial positioning; focal adhesion assembly and stability was decreased in Miro1−/−MEFs compared with Miro1+/+ MEFs. Consequently Miro1−/− MEFs migrated slower than control cells during both collective and single-cell migration. These data establish that Miro1-mediated mitochondrial positioning at the leading edge provides localized energy production that promotes cell migration by supporting membrane protrusion and focal adhesion stability.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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