Abstract
Peroxisomes are essential for a number of cellular functions, including reactive oxygen species metabolism, fatty acid β‐oxidation and lipid synthesis. To ensure optimal functionality, peroxisomal size, shape and number must be dynamically maintained; however, many aspects of how this is regulated remain poorly characterised. Here, we show that the localisation of Miro1 and Miro2—outer mitochondrial membrane proteins essential for mitochondrial trafficking—to peroxisomes is not required for basal peroxisomal distribution and long‐range trafficking, but rather for the maintenance of peroxisomal size and morphology through peroxisomal fission. Mechanistically, this is achieved by Miro negatively regulating Drp1‐dependent fission, a function that is shared with the mitochondria. We further find that the peroxisomal localisation of Miro is regulated by its first GTPase domain and is mediated by an interaction through its transmembrane domain with the peroxisomal‐membrane protein chaperone, Pex19. Our work highlights a shared regulatory role of Miro in maintaining the morphology of both peroxisomes and mitochondria, supporting a crosstalk between peroxisomal and mitochondrial biology.
Highlights
Peroxisomes are single-membrane bound organelles that are required for a wide range of essential metabolic pathways
To measure the extent of this peroxisomal localisation, thresholded GFP signal on catalase positive but Tom20 negative structures was quantified. Both GFPMiro1 and GFPMiro2 showed a significant enrichment of peroxisomal localisation over GFPTom70(1-70) (a GFP fusion protein of the mitochondria-targeting sequence of Tom70), highlighting a specific localisation of Miro to the peroxisomes and not a mislocalisation of outer mitochondrial membrane (OMM) proteins (Figure 1A-B)
We conclude that both Miro1 and Miro2 can localise to peroxisomes and that the transmembrane domain of Miro1 is critical for its interaction with Pex19
Summary
Peroxisomes are single-membrane bound organelles that are required for a wide range of essential metabolic pathways As sites of both the production and clearance of reactive oxygen species (ROS) as well as the biosynthesis of specific lipids (e.g. plasmalogens), peroxisomes are critical for cellular health. This is emphasised by loss-of-function mutations of key genes in peroxisomal biogenesis (PEX genes) leading to Zellweger spectrum disorders (Klouwer et al, 2015). Peroxisomes can be generated de novo by the combination of pre-peroxisomal vesicles from the endoplasmic reticulum and mitochondria (Agrawal and Subramani, 2016; Kim et al, 2006; Sugiura et al, 2017). The peroxisomal targeting of hFis and Mff is proposed to occur from the cytosol by the membrane protein chaperone, Pex, suggesting an axis whereby these proteins can be either targeted to the mitochondria or peroxisomes (Delille and Schrader, 2008)
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