Emerging roles for Mitochondrial Rho GTPases in tumor biology.

Mitochondrial Rho GTPases (MIRO1 and MIRO2) are primarily studied for their role as resident mitochondrial anchor proteins that facilitate mitochondria trafficking in neurons. However, it is now appreciated that these proteins have critical roles in cancer. In this review, we focus on examining the role of MIROs in cancer, including expression changes in tumors and the molecular mechanisms by which MIROs impact tumor cell growth, invasion, and metastasis. Additionally, we give an overview of how MIRO's functions in normal cells within the tumor microenvironment can support or inhibit tumor growth and metastasis. Although this is still an emerging field, the current consensus is that the MIROs primarily promote tumor progression of disparate tumor types. As mitochondrial proteins are now being targeted in the clinic, we discuss their potential as novel proteins to target in cancer.

Mitochondrial Fission and Fusion in Tumor Progression to Metastasis.

Mitochondria are highly dynamic organelles which can change their shape, via processes termed fission and fusion, in order to adapt to different environmental and developmental contexts. Due to the importance of these processes in maintaining a physiologically healthy pool of mitochondria, aberrant cycles of fission/fusion are often seen in pathological contexts. In this review we will discuss how dysregulated fission and fusion promote tumor progression. We focus on the molecular mechanisms involved in fission and fusion, discussing how altered mitochondrial fission and fusion change tumor cell growth, metabolism, motility, and invasion and, finally how changes to these tumor-cell intrinsic phenotypes directly and indirectly impact tumor progression to metastasis. Although this is an emerging field of investigation, the current consensus is that mitochondrial fission positively influences metastatic potential in a broad variety of tumor types. As mitochondria are now being investigated as vulnerable targets in a variety of cancer types, we underscore the importance of their dynamic nature in potentiating tumor progression.

MIRO2 Regulates Prostate Cancer Cell Growth via GCN1-Dependent Stress Signaling.

There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in metastatic prostate cancer compared with localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent androgen-independent or -sensitive prostate cancer, we showed that MIRO2 depletion impaired cell growth, colony formation, and tumor growth in mice. Network analysis of MIRO2's binding partners identified metabolism and cellular responses to extracellular stimuli as top overrepresented pathways. The top hit on our screen, General Control Nonderepressible 1 (GCN1), was overexpressed in prostate cancer, and interacted with MIRO2 in prostate cancer cell lines and in primary prostate cancer cells. Functional analysis of MIRO2 mutations present in patients with prostate cancer led to the identification of MIRO2 159L, which increased GCN1 binding. Importantly, MIRO2 was necessary for efficient GCN1-mediated GCN2 kinase signaling and induction of the transcription factor activating transcription factor 4 (ATF4) levels. Further, MIRO2's effect on regulating prostate cancer cell growth was mediated by ATF4. Finally, levels of activated GCN2 and ATF4 were correlated with MIRO2 expression in prostate cancer xenografts. Both MIRO2 and activated GCN2 levels were higher in hypoxic areas of prostate cancer xenografts. Overall, we propose that targeting the MIRO2-GCN1 axis may be a valuable strategy to halt prostate cancer growth. IMPLICATIONS: MIRO2/GCN1/GCN2 constitute a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth.