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.
Highlights
Peroxisomes are dynamic, multifunctional organelles that vary in size, number, and shape depending on cell type, environmental stimuli and metabolic demand 1, but the underlying molecular mechanisms which govern this versatility are not fully understood
We suggest that peroxisome-ER tethering is cell-type specific and that MIRO1/motor-mediated pulling forces can induce peroxisome proliferation in fibroblasts, whereas in COS-7 cells peroxisomes are dragged towards the cell periphery (Fig. 4B)
During the submission of our work, Okumoto et al (2017) 55 revealed that distinct MIRO1 splice variants show different targeting to mitochondria and peroxisomes in HEK cells, with MIRO1-variant 4 being more specific for peroxisomes
Summary
Peroxisomes are dynamic, multifunctional organelles that vary in size, number, and shape depending on cell type, environmental stimuli and metabolic demand 1, but the underlying molecular mechanisms which govern this versatility are not fully understood. Peroxisomes metabolically cooperate and physically interact with a variety of subcellular organelles including the ER, mitochondria, lipid droplets and other peroxisomes 4–6. These functions require peroxisome positioning and movement within eukaryotic cells. Loss of PEX11β was recently linked to spindle misorientation and peroxisome mislocalisation in mitosis causing imbalances in epidermal differentiation 16. These findings underline the importance of peroxisome multiplication, distribution and inheritance for cell fate decisions
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