Miro proteins and their role in mitochondrial transfer in cancer and beyond

Abstract

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.

HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia

“…Several studies have shown that the transferred mitochondria can exert their effect within a minimum of 45 cell passages (135 days) in vitro [ 53 ], while other studies discovered maintenance of acquired phenotype for at least 21 days [ 54 ]. The three common inducers of TNT formation typically work together: chemical or physical stressors, inflammatory conditions, and metabolic stress [ 55 ]. TNT formation can be promoted by hypoxia in various cancers, including ovarian and colon cancer [ 36 ].…”

HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia

“…Studies have shown that the effect of transferred mitochondria can be exerted within at least 45 cell passages (135 days) in vitro 53 , while others demonstrate maintenance of acquired phenotype for at least 21 days 54 . The three common causes of TNTs formation typically work together: chemical or physical stressors, in ammatory conditions, and metabolic stress 55 . The hypoxia present in various cancers can promote the formation of TNTs, such as ovarian or colon cancer 36 .…”

Transplanting Heterologous Mitochondria from Human Umbilical Vein Endothelial Cells Reduces the Malignancy of Melanoma Cells

“…In addition, the droplet-based microfluidic system in enhancing the transplantation of mitochondria was also reported [22]. In the molecular aspect, proteins such as Miro 1 and Miro 2 proteins were found to be involved in mitochondrial trafficking [23]. Therefore, the natural or artificial transfer of mitochondria were broadly discovered.…”