RHOT1/RHOT2 in Prostate Cancer: Mitochondrial Trafficking, Stress Signaling, Invasion, and Therapeutic Opportunities

Abstract

Mitochondrial biology has emerged as an important determinant of cancer progression, encompassing not only oxidative metabolism and redox  homeostasis but also mitochondrial dynamics, intracellular positioning, signaling, and communication with the cytoskeleton. RHOT1 and RHOT2, encoding the mitochondrial Rho GTPases MIRO1 and MIRO2, respectively, are outer mitochondrial membrane proteins that regulate mitochondrial trafficking and positioning. Although structurally related, accumulating evidence indicates that MIRO1 and MIRO2 can perform non-redundant functions in cancer. Among the two proteins, RHOT2/MIRO2 has the strongest direct evidence in prostate cancer (PCa). MIRO2 is overexpressed in advanced and metastatic PCa, is associated with adverse clinical outcomes, and promotes prostate cancer cell growth through a MIRO2–GCN1–ATF4 stress-signaling pathway. More recent work has established an additional role for MIRO2 in prostate cancer invasion and metastasis through interaction with unconventional myosin 9B (MYO9B) and suppression of RhoA activity. By contrast, direct evidence connecting RHOT1/MIRO1 to prostate tumorigenesis remains limited, and experimental depletion of MIRO1 did not reproduce the growth or stress-signaling phenotypes observed following MIRO2 depletion in PCa models. Nevertheless, MIRO1 has well-established roles in Ca²⁺-dependent mitochondrial trafficking, mitochondrial–cytoskeletal coupling, and intercellular mitochondrial transfer, providing several plausible mechanisms by which RHOT1 could influence PCa biology. This review summarizes the molecular biology of RHOT1/MIRO1 and RHOT2/MIRO2, evaluates their current evidence base in prostate cancer, discusses their connections with mitochondrial dynamics, metabolic stress, hypoxia, invasion and metastasis, and identifies major questions that must be addressed before MIRO proteins can be considered clinically actionable targets in PCa.