Lipid metabolism is essential for eukaryotic cells to normally function. To adapt to different nutritional and environmental changes, lipids are distributed to different organelles, depending on their cellular role. For example, lipids are distributed to mitochondria and peroxisomes for beta-oxidation, to the endoplasmic reticulum for lipid synthesis, the lysosome for the degradation and recycling of complex lipids, and lipid droplets for storage. These organelles are connected to each other, via tightly coordinated interactions that allow the cell to control lipid metabolism. One of the interactions that remains obscure is the nature of the contact sites between lipid droplets and peroxisomes. In this preprint, the team of Lippincott-Schwartz at Janelia Research Campus describes the molecular component of the tether between peroxisomes and lipid droplets (1).
Lipid droplets store neutral lipids that, when needed, are transported for their use to other locations in the cells. The peroxisomes are crucial organelles for lipid metabolism, involved in the beta-oxidation of fatty acids (FAs), ether lipid synthesis and branched-chain fatty acid oxidation, among others. The interaction between peroxisomes and lipid droplets has already been reported (2), but the molecular tether that allow lipid transport between them had been a mystery until now.
The group of Lippincott-Schwartz combined state-of-the-art imaging techniques, one the distinctive signatures of the Janelia research campus, to describe the nature of this tether. M1 Spastin, an isoform of the Spastin protein, and ABCD1, a peroxisomal transporter of fatty acids whose mutation causes X-linked adrenoleukodystrophy, forms a tether between peroxisomes and lipid droplets. This was observed by the increased number of contacts between peroxisomes and lipid droplets after M1 Spastin overexpression. A meticulous study of the function of the different domains of M1 Spastin led them to reveal an essential role of the MIT (microtubule interacting domain) domain of M1 Spastin in FA trafficking from lipid droplets to the peroxisome, and the AAA ATPase domain in the generation of the contact sites between these two organelles. They show that M1 Spastin gets inserted into the lipid monolayer of lipid droplets, but not into the peroxisome.
Besides the role of M1 Spastin in the tethering of peroxisomes and lipid droplets, they also gain mechanistic insight into how fatty acids are transported from lipid droplets to peroxisomes. This is mediated by the ESCRT-III proteins, IST1 (Increased sodium tolerance 1) and CHMP1B (Charged multivesicular body protein 1B), that somehow may change the curvature of the lipid droplet membrane. These ESCRT-III proteins are recruited to lipid droplets by the MIT domain of M1 Spastin.
Finally, they link defects in formation of this complex to disease. Mutations in M1 Spastin causes hereditary spastic paraplegia (HSP) (3), with a phenotype that partially overlaps the phenotype of X-linked adrenoleukodystrophy patients, caused by mutations in ABCD1, the peroxisomal component of this tether complex. They observed that the formation of the contact site between peroxisomes and lipid droplets, and the trafficking of fatty acids between them were abolished in cells expressing the pathogenic M1 SpastinK388R mutation. Moreover, lipid peroxidation was increased in cells expressing this mutation, and decreased when M1 Spastin was overexpressed. This led the authors to hypothesize that the trafficking of fatty acids from lipid droplets to peroxisomes is important to eliminate the excess of lipid peroxidation, which has been demonstrated to be detrimental to different cellular functions, and involved in the pathogenesis of many diseases (4).
What I liked about the study
What I really liked about this study is that it reveals the identity of the components of the tether between peroxisomes and lipid droplets (Figure 1). This is a milestone for the study of the pathogenesis of many diseases related to fatty acid metabolism, which involves peroxisomal and/or lipid droplet dysfunction. Together, a combination of astonishing microscopy and elegant experimental design led to an important discovery for the lipid metabolism field.
Figure 1. Model for the tethering between peroxisomes and lipid droplets, proposed by the authors (corresponds to Figure 7E in the preprint). Obtained with the permission from the authors.
- Chang C-L, Weigel A V., Ioannou MS, Pasolli HA, Xu CS, Peale DR, Shtengel G, Freeman M, Hess HF, Blackstone C, Lippincott-Schwartz J (2019) Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III. bioRxiv:544023.
- Valm AM, Cohen S, Legant WR, Melunis J, Hershberg U, Wait E, Cohen AR, Davidson MW, Betzig E, Lippincott-Schwartz J (2017) Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature 546(7656):162–167.
- Blackstone C (2018) Hereditary spastic paraplegia. Handbook of Clinical Neurology, pp 633–652.
- Mylonas C, Kouretas D Lipid peroxidation and tissue damage. In Vivo 13(3):295–309.
Posted on: 22nd April 2019 , updated on: 23rd April 2019Read preprint
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