A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

Abstract

Peroxisomes are dynamic organelles which fulfil essential roles in lipid and ROS metabolism. Peroxisome movement and positioning allows interaction with other organelles and is crucial for their cellular function. In mammalian cells, such movement is microtubule‐dependent and mediated by kinesin and dynein motors. The mechanisms of motor recruitment to peroxisomes are largely unknown, as well as the role this plays in peroxisome membrane dynamics and proliferation. Here, using a combination of microscopy, live‐cell imaging analysis and mathematical modelling, we identify a role for Mitochondrial Rho GTPase 1 (MIRO1) as an adaptor for microtubule‐dependent peroxisome motility in mammalian cells. We show that MIRO1 is targeted to peroxisomes and alters their distribution and motility. Using a peroxisome‐targeted MIRO1 fusion protein, we demonstrate that MIRO1‐mediated pulling forces contribute to peroxisome membrane elongation and proliferation in cellular models of peroxisome disease. Our findings reveal a molecular mechanism for establishing peroxisome‐motor protein associations in mammalian cells and provide new insights into peroxisome membrane dynamics in health and disease.

Miro1 – the missing link to peroxisome motility

“…In contrast to these findings, we and Covill-Cooke and colleagues observed the targeting of Miro1 variant 1 to peroxisomes and mitochondria in COS-7 and mouse embryonic fibroblasts (MEFs) [11,14]. This variant, which lacks insert 1, was also shown to interact with Pex19 in a TMD and tail dependent manner.…”

“…In agreement with this, similar peroxisome accumulations have been previously observed using an inducible cargo assay where kinesin motors are artificially tagged to peroxisomes in a regulated and inducible manner [25]. Furthermore, overexpression of wild type Miro1 or a constitutively active mutant for the 1 st GTPase domain of Miro1, induced a significant increase in peroxisome fast-directed movement [11,13], while silencing of Miro1 significantly decreased peroxisome motility [13]. These results suggest that, analogous to Miro1’s role at mitochondria, peroxisomal Miro1 regulates microtubule-dependent motility of this organelle (Figure 1).…”

“…Overexpression of Miro1 (wild-type and constructs mutated in the first GTPase domain) in COS-7 and HeLa cells induced a redistribution of peroxisomes to the cell periphery, an effect that was inhibited by treating the cells with nocodazole, a microtubule depolymerizing drug [11,13]. These results suggest a potential role for Miro1 in peroxisome motility, similar to its role in mitochondrial motility (Figure 1).…”

“…As shown in all three studies, Miro1 is no exception to this rule [11,13,14]. However, the conclusions on how this interaction is mediated and which isoforms of Miro1 are targeted to peroxisomes differ between studies.…”

“…Strikingly, little is known about the recruiting factors for these motors and how peroxisome motility is regulated. Recently, we and others have shown that Miro1, an atypical Ras GTPase, is targeted to peroxisomes in mammalian cells, where it regulates peroxisome motility (Figure 1) [11–14]. …”