Peroxisomes were only discovered in the 1960s, the oxidative organelle have since been found to be essential for human health and development.
An important feature of eukaryotic cells is the presence of membrane-bound compartments, or organelles. Organelles are the functional units of a cell, as they create distinct optimised micro-environments which allow the cell to perform a multitude of metabolic reactions required to sustain life. However, organelles cannot work as isolated entities. For the entire cell to function as a unit, a coordinated interplay between specialised organelles must occur.
Recent advances in cell biology have uncovered that organelle interplay is often mediated through membrane contact sites, whereby two (or more) organelles come into close apposition allowing the exchange of metabolites, lipids and proteins (Fig. 1). It is evident now that membrane contacts are central to cell physiology.
Moreover, alterations of membrane contacts have been observed in various diseases. An important and challenging question in modern cell biology is now to characterise the components and functions of membrane contact sites between organelles, to understand how they are regulated, and what physiological roles they play in human health and disease.
Peroxisomes take centre stage
Peroxisomes were only discovered in the 1960s and remained enigmatic and little studied for many years. Since their discovery several interesting and unexpected features of peroxisomes have been revealed.1 Peroxisomes are highly dynamic, multifunctional, oxidative organelles which are ubiquitously found in mammals, plants and fungi. It is now evident that they have a key role in in the metabolism of cellular lipids and reactive oxygen species (ROS) and are essential for human health and development.2 These functions require dynamic interactions and cooperation with many organelles involved in cellular lipid metabolism such as the endoplasmic reticulum (ER), mitochondria, lipid droplets and lysosomes (Figs. 1, 2).2,3
Peroxisomes cooperate with lipid droplets and mitochondria to break down dietary fatty acids. Lipid droplets store fatty acids, but to be harvested for energy the fatty acids must be imported into oxidative organelles such as mitochondria and peroxisomes, where they are metabolised through β-oxidation. Certain fatty acids (e.g., very-long-chain fatty acids or phytanic acid from dairy products, ruminant animal fats, and certain fish) can only be degraded in peroxisomes and are toxic when they accumulate. Peroxisomes also need to interact with the ER to effectively synthesise ether-phospholipids, which have important functions in the brain (e.g., myelin sheath lipids) or docosahexaenoic acid, a modulator of neuronal function. Their interaction with lysosomes, the degradation and recycling centre of the cell, has been linked to cellular cholesterol homeostasis.4 Moreover, peroxisomes in the liver are involved in the synthesis of bile acids which depends on metabolic cooperation between the cytosol, mitochondria, ER and peroxisomes.2
In addition to their metabolic functions, peroxisomes are now increasingly recognised as important intracellular signalling platforms (for example in redox signalling) which modulate physiological and pathological processes such as innate immunity, inflammation, and cell fate decision.5,6 Peroxisomes are important for the development of the brain and fulfil neuroprotective functions preventing axonal degradation, demyelination and neuroinflammation. Recent findings have linked them to aging and the development of chronic diseases such as neurodegeneration, diabetes, and cancer. In addition, peroxisomes are involved in anti-viral signalling and the combat of pathogens. Peroxisomes are increasingly recognised as targets for pathogens (including viruses) to exploit their lipid metabolising functions for their own benefits, or to block the anti-viral defence of the cell.
Research into peroxisome-organelle interplay
Although close peroxisome-organelle associations were already observed decades ago in ultrastructural studies, the identification of the molecular machinery involved and its physiological function only began recently (Fig. 2).3,7,8 Our laboratory at the University of Exeter is expanding the general understanding of the molecular mechanisms underlying peroxisome dynamics and biogenesis and their relation to inter-organelle cooperation, cell physiology, and disease. How peroxisome-ER contacts are formed and regulated is still poorly understood, but in a recent study we identified the first proteins involved in their formation and maintenance. We discovered that the peroxisomal membrane protein ACBD5 (a so-called acyl-CoA-binding domain protein, which can bind activated fatty acids) directly interacts with the ER-resident membrane protein VAPB by specific motifs.9 These proteins form a molecular tether which brings peroxisomes and the ER in close apposition and enables the formation of membrane contact sites.
An estimated 70-80% of peroxisomes are closely associated with the ER highlighting the importance of those contacts in mammalian cells. We demonstrated that these membrane contact sites are dependent on ACBD5-VAPB interactions and are required for the metabolic cooperation between peroxisomes and the ER in lipid synthesis, but also regulate peroxisome motility and distribution in the cell as well as the transfer of lipids from the ER to peroxisomes for membrane expansion and subsequent growth and division/multiplication of peroxisomes. Meanwhile, the first patients with a genetic ACBD5 deficiency were identified, which present with retinal dystrophy and progressive neurodegeneration.10,11 Patient cells show a reduction in ether-phospholipids, and an accumulation of very-long-chain fatty acids (VLCFAs) due to a dysfunction in peroxisomal β-oxidation.12 We hypothesise that the ACBD5-VAPB tether contributes to the formation of a peroxisome-ER hub which may be crucial for the capture, activation and channelling of fatty acids to coordinate lipid metabolism at the ER-peroxisome interface.7
Recent studies in the rapidly growing field of membrane contacts and organelle interaction have identified a role for the lysosomal protein synaptotagmin VII (Syt7) in the interaction of lysosomes with peroxisomes and in cholesterol transport between the organelles.4 Furthermore, a role for the lipid droplet protein spastin in the tethering of lipid droplets to peroxisomes via the peroxisomal fatty acid transporter ALDP and in fatty acid trafficking to peroxisomes was revealed.13 Spastin is involved in hereditary spastic paraplegia, a group of inherited neurological disorders that are characterised by progressive weakness and spasticity (stiffness) of the legs.
These studies so far revealed that inter-organelle communication at peroxisome-organelle contacts regulates several physiological processes including lipid metabolism, membrane lipid exchange, peroxisome biogenesis, and motility/positioning. Despite their fundamental importance to cell metabolism, mechanisms that regulate peroxisome-organelle contacts are poorly understood. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in disease aetiology. As peroxisomes, which contribute to cellular redox balance, breakdown of toxic lipids and combat of pathogens, have protective functions, a better understanding of how to modulate peroxisome-organelle interplay and cooperation, both on the organelle and the signalling level, can open new avenues for cell protection and improvement of cell performance under certain stress conditions.
As outlined, peroxisomes (and other subcellular organelles) cannot function as isolated entities; in contrast, they are integrated into a complex network of interacting and cooperating organelles, which is just beginning to emerge. A challenge ahead is to identify and characterise novel molecules involved in organelle tethering and contact site formation, and to reveal the physiological functions of organelle contacts and the mechanisms which mediate lipid transfer, metabolite exchange and signalling between interacting organelles. This will require new screening approaches and probes (e.g. to monitor lipid transfer), but also multidisciplinary approaches which combine expertise and techniques from different disciplines such as molecular cell biology, biophysics, proteomics, lipidomics, metabolomics and sophisticated imaging and quantification techniques. A first successful approach is the Marie Curie Initial Training Network PerICo (Peroxisome Interactions and Communication) (H2020-MSCA-ITN-2018 812968) (https://itn-perico.eu/) focusing on the identification and functional characterisation of peroxisomal membrane contact sites and transporter with strong interdisciplinary links between industry, life and medical sciences.
The disruption of organelle contacts has been linked to disease, for example to neurodegeneration, but knowledge about the role and importance of membrane contacts in human health and disease is scarce. It will therefore be important to reveal how the formation of organelle contacts is regulated to control their dynamics, and to investigate how organelle contacts change under pathophysiological conditions. A challenge is to diagnose organelle contact-related diseases, as symptoms can be expected to be complex and are not yet well characterised. Importantly, tether proteins can have multiple functions (e.g. in metabolite transfer), and tethering can be redundant with multiple tether complexes involved. Organelle contacts may also influence the development of common, age-related disorders such as neurodegenerative diseases. An improved understanding of organelle cooperation and crosstalk may lead to therapeutic approaches allowing specific targeting and modulation of tethering complexes to combat degenerative diseases. This will require close cooperation between clinical, diagnostic and fundamental research-driven laboratories. There is no doubt that research on organelle interplay and membrane contacts is an exciting, rapidly developing field, which will greatly impact on our understanding of human cell biology, health and disease.
Michael Schrader, PhD
Professor and Chair in Cell Biology & Cytopathology
University of Exeter
+44 (0)1392 725850
Please note, this article will appear in issue 32 of SciTech Europa Quarterly, which is available to read now.