Genome-Wide Localization Study of Yeast Pex11 Identifies Peroxisome–Mitochondria Interactions through the ERMES Complex

Abstract

Pex11 is a peroxin that regulates the number of peroxisomes in eukaryotic cells. Recently, it was found that a mutation in one of the three mammalian paralogs, PEX11β, results in a neurological disorder. The molecular function of Pex11, however, is not known. Saccharomyces cerevisiae Pex11 has been shown to recruit to peroxisomes the mitochondrial fission machinery, thus enabling proliferation of peroxisomes. This process is essential for efficient fatty acid β-oxidation. In this study, we used high-content microscopy on a genome-wide scale to determine the subcellular localization pattern of yeast Pex11 in all non-essential gene deletion mutants, as well as in temperature-sensitive essential gene mutants. Pex11 localization and morphology of peroxisomes was profoundly affected by mutations in 104 different genes that were functionally classified. A group of genes encompassing MDM10, MDM12 and MDM34 that encode the mitochondrial and cytosolic components of the ERMES complex was analyzed in greater detail. Deletion of these genes caused a specifically altered Pex11 localization pattern, whereas deletion of MMM1, the gene encoding the fourth, endoplasmic-reticulum-associated component of the complex, did not result in an altered Pex11 localization or peroxisome morphology phenotype. Moreover, we found that Pex11 and Mdm34 physically interact and that Pex11 plays a role in establishing the contact sites between peroxisomes and mitochondria through the ERMES complex. Based on these results, we propose that the mitochondrial/cytosolic components of the ERMES complex establish a direct interaction between mitochondria and peroxisomes through Pex11.

The Emerging Network of Mitochondria-Organelle Contacts

“…In yeast, peroxisomes are major sites of fatty acid β-oxidation, the product of which, acetylcarnitine, can be used to make acetyl-CoA and power the TCA cycle and drive respiration. Two recent studies have found that peroxisomes are juxtaposed to ERMES marked ER-mitochondria contacts and the pyruvate decarboxylase complex in the mitochondrial matrix, which generates the hub metabolite, acetyl-CoA (Cohen et al, 2014; Mattiazzi Usaj et al, 2015). The connection between mitochondria and peroxisomes is mediated, in part, by interactions between the mitochondrial localized ERMES subunit, Mdm34 and Pex11, which has been implicated as a peroxisomal membrane shaping protein.…”

Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

“…Mdm10, Mdm12, and Mdm34 were required for proper localization of Pex11, whereas the absence of the ER-resident ERMES component, Mmm1, did not affect Pex11 localization. Pex11 was shown to physically interact with Mdm34 and was required for formation of contact sites between peroxisomes and mitochondria (101).…”

Signaling dynamics and peroxisomes

“…However, how the regulation of peroxisomes is integrated with other organelles, especially the ER, is poorly understood. Further evidence of the intimate association between peroxisomes, the ER, and mitochondria comes from a recent systems biology screen in yeast that uncovered an association between the ER and mitochondrion encounter structure (ERMES) and peroxisomes [30]. Peroxisomes themselves are intimately associated physically with mitochondria [31,32] and can be formed from the ER [33–35].…”