Molecular complex coordinating peroxisome morphogenesis in mammalian cells

Abstract

Peroxisomal division comprises three stages: elongation, constriction, and fission. Potential candidates thus far studied for the factors involved in these stages include Pex11pβ, dynamin-like protein 1 (DLP1), mitochondrial fission factor (Mff), and Fission 1 (Fis1). A poly-unsaturated fatty acid of peroxisomal β-oxidation metabolites, docosahexaenoic acid (C22:6n-3), augments hyper-oligomerization of Pex11pβ that gives rise to peroxisomal elongation, a prerequisite for subsequent fission and peroxisome division. Translocation of DLP1, a member of the large GTPase family, from the cytosol to peroxisomes is a prerequisite for membrane fission. However, the molecular machinery for peroxisomal targeting of DLP1 remains elusive. Mff is also localized to peroxisomes, especially at the membrane-constricted regions of elongated peroxisomes. Knockdown of Mff abrogates the fission stage of peroxisomal division and fails to recruit DLP1 to peroxisomes, while ectopic expression of Mff increases the peroxisomal targeting of DLP1. Co-expression of Mff and Pex11pβ increases peroxisome abundance. Overexpression of Mff also increases the interaction between DLP1 and Pex11pβ, which knockdown of Mff, but not Fis1, abolishes. Moreover, Pex11pβ interacts with Mff in a DLP1-dependent manner. Mff contributes to the peroxisomal targeting of DLP1 and plays a key role in the fission of the peroxisomal membrane by acting in concert with Pex11pβ and DLP1. The investigations performed to date suggest that a functional complex comprising Pex11pβ, Mff, and DLP1 promotes Mff-mediated fission during peroxisomal division. With regard to peroxisome morphogenesis, we address recent issues and findings and propose a model for peroxisome division.