Mind the Organelle Gap - Peroxisome Contact Sites in Disease

Abstract

The eukaryotic cell is organized as a complex grid system where membrane-bound cellular compartments, organelles, must be localized to the right place at the right time. One way to facilitate correct organelle localization and organelle cooperation is through membrane contact sites, areas of close proximity between two organelles that are bridged by protein/lipid complexes. It is now clear that all organelles physically contact each other. The main focus of this review is contact sites of peroxisomes, central metabolic hubs whose defects lead to a variety of diseases. New peroxisome contacts, their tethering complexes and functions have been recently discovered. However, if and how peroxisome contacts contribute to the development of peroxisome-related diseases is still a mystery.

Keywords: contact sites; endoplasmic reticulum; mitochondria; organelles; peroxisomal disorders; peroxisomes; tethering.

Figure 1. The cellular peroxisome contact site grid

In the past five years several new peroxisome contact sites have been identified, and their molecular components and functions are now being explored. In mammalian cells, ACBD5 and ACBD4 have been shown to interact with the ER proteins VAPA and VAPB, in a contact site suggested to regulate peroxisome biogenesis and metabolism. Peroxisomes have also been shown to interact with lysosomes for cholesterol trafficking (SYT7-PI(4,5)P₂). In S. cerevisiae, peroxisomes have been shown to interact with the ER for inheritance during cell division (Pex3-Inp1-Pex3) and with mitochondria to perform metabolic functions (Pex34-?; Fzo1-Fzo1/?; Pex11-Mdm34). In the filamentous fungus U. maydis, peroxisomes form a contact site with endosomes that allows then to hitchhike and move through the cell (?-PxdA-?).

Figure 2. Potential involvement of peroxisome contact sites in peroxisomal disorders

Healthy human cells have a large population of round, well distributed peroxisomes. In classical peroxisome disorders, these organelles can be completely absent (defects in PEX3, PEX16 and PEX19), reduced and/or enlarged (defects in DBP, ACOX1), or can have altered shape and distribution (defects in MFF, DLP1 and PEX11β). Notably, alterations in peroxisome number or morphology could also be a secondary effect of a defect in contact sites. In these cases, the defect can still be diagnosed microscopically but identifying its genetic cause will require further investigation. We hypothesize that in some cases of peroxisomal disorders peroxisome shape, size and distribution will appear normal microscopically, however alterations in the number of interactions with specific organelles, or changes in the balance of interaction with several organelles will be the cause of the disease. New tools should be developed to diagnose these cases at the cellular level.