Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes

Peroxisomes—tiny intracellular organelles that contain metabolic enzymes—are generated in mammalian cells by the fusion of structures that arise from both mitochondria and the endoplasmic reticulum. Mitochondria have a role in peroxisome formation Peroxisomes are home to a variety of metabolic enzymes. These membrane-bound organelles work closely with mitochondria, exchanging metabolites for completion of a number of enzymatic cascades. Peroxisomes can either appear anew or divide from pre-existing organelles, specifically the endoplasmic reticulum. Intrigued by the knowledge that in the absence of peroxisomes, several integral peroxisomal membrane proteins are imported into the mitochondria of mammalian cells, Heidi McBride and co-workers investigate the role of mitochondria in the formation of peroxisomes. They find that in mammalian cells, peroxisomes are the product of structures that arise from not just the endoplasmic reticulum, but also from mitochondria. Peroxisomes function together with mitochondria in a number of essential biochemical pathways, from bile acid synthesis to fatty acid oxidation 1 . Peroxisomes grow and divide from pre-existing organelles 2 , but can also emerge de novo in the cell 3 . The physiological regulation of de novo peroxisome biogenesis remains unclear, and it is thought that peroxisomes emerge from the endoplasmic reticulum in both mammalian and yeast cells 4 . However, in contrast to the yeast system 5 , 6 , 7 , 8 , a number of integral peroxisomal membrane proteins are imported into mitochondria in mammalian cells in the absence of peroxisomes, including Pex3, Pex12, Pex13, Pex14, Pex26, PMP34 and ALDP 9 , 10 , 11 , 12 , 13 , 14 , 15 . Overall, the mitochondrial localization of peroxisomal membrane proteins in mammalian cells has largely been considered a mis-targeting artefact in which de novo biogenesis occurs exclusively from endoplasmic reticulum-targeted peroxins 16 . Here, in following the generation of new peroxisomes within human patient fibroblasts lacking peroxisomes, we show that the essential import receptors Pex3 and Pex14 target mitochondria, where they are selectively released into vesicular pre-peroxisomal structures. Maturation of pre-peroxisomes containing Pex3 and Pex14 requires fusion with endoplasmic reticulum-derived vesicles carrying Pex16, thereby providing full import competence. These findings demonstrate the hybrid nature of newly born peroxisomes, expanding their functional links to mitochon