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Peroxisomes take shape

Subjects

Key Points

  • Peroxisomes are dynamic and diverse organelles that are found in nearly all eukaryotic cells, and the disruption of their function is linked to peroxisome-related diseases. During biogenesis, peroxisomal membrane and matrix proteins are imported into peroxisomes, and this is mediated by the capacity of peroxisomes to import protein complexes.

  • Two mechanisms of peroxisome biogenesis, de novo generation and fission from pre-existing peroxisomes, have been characterized, and one possibility is that they are conditionally and coordinately regulated.

  • The regulation of peroxisome dynamics is mediated by multifunctional peroxins, which have potential roles in coordinating peroxisome proliferation (by de novo generation and fission) with inheritance and degradation to control peroxisome size and abundance. Exciting roles of peroxins in peroxisome differentiation, motility and inheritance are also emerging.

  • An important outstanding challenge is to elucidate how the processes that contribute to peroxisome dynamics are regulated and coordinated, and systems approaches such as mathematical modelling will be essential for tackling this.

Abstract

Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health.

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Figure 1: Peroxisome dynamics.
Figure 2: Direct targeting of proteins to peroxisomes.
Figure 3: Peroxisomes can form through two pathways.

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Acknowledgements

The work in the authors' laboratory was supported by the US National Institutes of Health Grants P50 GM076547, U01GM098256, U54GM103511 and GM075152. The authors thank the Luxembourg Centre for Systems Biomedicine, the Life Sciences Discovery Fund and the University of Luxembourg for support.

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Glossary

Peroxisome inheritance

The active recruitment of peroxisomes from a mother cell to a daughter cell during cell division, and the retention of peroxisomes in the mother cell and the bud to ensure equitable distribution of peroxisomes between the two cells.

Peroxins

Proteins that are encoded by PEX genes and that are involved in peroxisome biogenesis (excluding transcriptional regulators).

PEX genes

Genes encoding proteins that are involved in peroxisome biogenesis (excluding those involved in transcriptional regulation). The numbers reflect the order in which they were identified.

Peroxisome biogenesis disorders

(PBDs). A group of developmental brain disorders with a prevalence of 1:50,000. These disorders are caused by mutations in peroxin (PEX) genes which lead to dysfunctional peroxisome biogenesis. PBDs, or Zellweger syndrome spectrum (ZSS), include, in decreasing order of severity, Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile refsum disease (IRD).

PTS1

The carboxy-terminal peroxisomal targeting signal 1 (with the sequence (Ser/Ala/Cys)(Lys/Arg/His)(Leu/Met/Ile)) is found on most matrix proteins.

PTS2

The peroxisomal targeting signal type 2 (with the sequence (Arg/Lys)(Leu/Val/Ile)(Xaa)5(His/Gln)(Leu/Arg); where Xaa represents any amino acid) is located near the amino terminus of some peroxisomal matrix proteins. It is found much less commonly than PTS1 motifs.

Transient pore hypothesis

A model of matrix protein import into peroxisomes. It involves the transient existence of a protein-conducting translocon that assembles after docking of the receptor–cargo complex to peroxisomes and disassembles after translocation.

Membrane invagination model

A model of matrix protein import into peroxisomes. At the site where receptor–cargo complexes dock on the surface of a peroxisome, the membrane invaginates and 'pinches off' to form an intraperoxisomal vesicle that is surrounded by a single membrane which is later degraded to release its contents into the peroxisome.

Preimplex hypothesis

A model of the early steps of matrix protein import into peroxisomes. Multiple peroxisomal PEX5 receptors interact with multiple cargoes in the cytoplasm to form so-called preimplexes, which are necessary for the efficient import of cargo into peroxisomes.

RING

A zinc-finger-type domain that is found in many proteins involved in the ubiquitylation pathway, including RING finger group proteins in peroxisomal membranes (peroxin 2 (PEX2), PEX10 and PEX12).

AAA-type ATPase

A large family of ATPases, including peroxin 1 (PEX1) and PEX6, that contain an ATPase domain. These proteins can drive remodelling or translocation of macromolecules through ATP hydrolysis.

Membrane PTS

(mPTS). A targeting signal of peroxisomal membrane proteins. The consensus sequence is not well defined and may be discontinuous. It can consist of basic amino acids that have been predicted to form an α-helix that is either adjacent to a transmembrane segment or in a matrix-facing loop.

Peroxisomal ER

Subdomain of the endoplasmic reticulum that is the site of peroxisome formation.

Preperoxisomal vesicles

Vesicles that have budded from the endoplasmic reticulum and are destined to become mature peroxisomes.

Mature peroxisomes

A functional peroxisome that is capable of matrix protein import.

Dynamin-related proteins

(DRPs). Primarily cytosolic GTPases that are involved in membrane fusion and fission. They are recruited to peroxisomal membranes by tail-anchored membrane receptor proteins called DRP-binding proteins.

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Smith, J., Aitchison, J. Peroxisomes take shape. Nat Rev Mol Cell Biol 14, 803–817 (2013). https://doi.org/10.1038/nrm3700

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