Peroxisomes have important functions for lipid and hydrogen peroxide metabolism, and, in response to stimuli, undergo dynamic changes in their number through elongation and division. This involves the peroxisomal membrane protein PEX11β and the mitochondrial factors FIS1 and MFF, which recruit the GTPase DRP1 for organelle fission. Although MFF appears to be essential for peroxisome fission, the exact role of FIS1 has been unclear. In this work, Michael Schrader and colleagues (T. A. Schrader et al., 2022) now identify the existence of parallel pathways of peroxisome division in mammalian cells, depending on either MFF or PEX11β. Indeed, they show that in cells that lack MFF, PEX11β is able to drive peroxisome division, which requires FIS1 and involves its interaction with the C-terminal tail of PEX11β. Furthermore, PEX11β can also induce mitochondrial fission when it is targeted to mitochondria. Conversely, overexpression of MFF in fibroblasts derived from PEX11β-deficient patients, which exhibit elongated peroxisomes, is sufficient to restore normal peroxisome morphology without a requirement for FIS1. Taken together, these findings point to the existence of two pathways for peroxisome fission, one that involves MFF, and a second MFF-independent route that depends on PEX11β and FIS1, and also raise the possibility that modulating the levels of MFF or PEX11β could represent a therapeutic option to overcome the defects in peroxisome dynamics observed in associated diseases.
