Mitochondria are organelles essential for
tumor cell proliferation and
metastasis. Although their main cellular function, generation of energy in the form of
ATP is dispensable for
cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that
cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive
pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for
tumor cell migration, invasion and
metastasis. The spatial positioning and transport of mitochondria involves Miro
proteins from a subfamily of
small GTPases, localized in outer mitochondrial membrane. Miro
proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor
proteins. In this review, we discuss the function of Miro
proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro
proteins in nanotube-mediated transfer as well as in
cancer cell migration and
metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.