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.

Keywords: Miro; cancer; intercellular transfer; metastasis; migration; mitochondria; respiration.

FIGURE 1

Mechanism of mitochondrial transport between two cells connected via TNTs. (A) Tunneling nanotube (TNT) formation between donor and acceptor cell could be pronounced by oxidative and metabolic stress or inflammatory conditions. Healthy mitochondria from the donor cell (left) move to a cancer cell (right) with damaged mitochondria. Mitochondria from cancer cells are possibly transported in opposite directions via TNTs. Mitochondrial transport in TNTs requires molecular motors that move the organelles along tubulin or actin filaments. It cannot be excluded that filaments are continuous from the donor cell into the TNT. (B) In the donor cell, mitochondria have to be transported towards the cell periphery into the base of TNTs. Peripheral localization of mitochondria is governed by kinesin or myosin motor proteins associated with microtubules or actin filaments respectively, tethered by Miro proteins. (C) Inside TNTs, healthy mitochondria are transported presumably along microtubules by kinesin motor with the assistance of TRAK adaptor and Miro, or along actin filaments by myosin with the assistance of Miro proteins. Damaged mitochondria could be possibly moved in the opposite direction by dynein with the assistance of Miro protein. (D) In the acceptor cell, imported mitochondria need to “switch the tracks” to be transported further within the cell. After import, mitochondria can establish functional connections with the nucleus (by means of nucleus-associated mitochondrial structures, NAMS), endoplasmic reticulum (ER-mitochondria encounter structures, ERMCS) and other organelles. The figure was created utilizing elements from Servier Medical Art (Creative Common Attribution 3.0 Generic License, https://smart.servier.com/).