The endoplasmic reticulum and mitochondria are main hubs of eukaryotic membrane biogenesis that rely on lipid exchange via membrane contact sites1-3, but the underpinning mechanisms remain poorly understood. In yeast, tethering and lipid transfer between the two organelles is mediated by the endoplasmic reticulum-mitochondria encounter structure (ERMES), a four-subunit complex of unresolved stoichiometry and architecture4-6. Here we determined the molecular organization of ERMES within Saccharomyces cerevisiae cells using integrative structural biology by combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling. We found that ERMES assembles into approximately 25 discrete bridge-like complexes distributed irregularly across a contact site. Each bridge consists of three synaptotagmin-like mitochondrial lipid binding protein domains oriented in a zig-zag arrangement. Our molecular model of ERMES reveals a pathway for lipids. These findings resolve the in situ supramolecular architecture of a major inter-organelle lipid transfer machinery and provide a basis for the mechanistic understanding of lipid fluxes in eukaryotic cells. 

In situ architecture of the ER-mitochondria encounter structure

De-centralizing the Central Dogma: mRNA translation in space and time.

Identification of both stable and transient interactions is essential for understanding protein function and regulation. While assessing stable interactions is more straightforward, capturing transient ones is challenging. In recent years, sophisticated tools have emerged to improve transient interactor discovery, with many harnessing the power of evolved biotin ligases for proximity labelling. However, biotinylation-based methods have lagged behind in the model eukaryote, Saccharomyces cerevisiae, possibly due to the presence of several abundant, endogenously biotinylated proteins. In this study, we optimised robust biotin-ligation methodologies in yeast and increased their sensitivity by creating a bespoke technique for downregulating endogenous biotinylation, which we term ABOLISH (Auxin-induced BiOtin LIgase diminiSHing). We used the endoplasmic reticulum insertase complex (EMC) to demonstrate our approaches and uncover new substrates. To make these tools available for systematic probing of both stable and transient interactions, we generated five full-genome collections of strains in which every yeast protein is tagged with each of the tested biotinylation machineries, some on the background of the ABOLISH system. This comprehensive toolkit enables functional interactomics of the entire yeast proteome. 

A toolbox for systematic discovery of stable and transient protein interactors in baker's yeast

Peroxisomes are organelles containing different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. Peroxisome biogenesis is controlled by a family of proteins called peroxins, which are required for peroxisomal membrane formation, matrix protein transport, and division. Mutations of peroxins cause metabolic disorders called peroxisomal biogenesis disorders, among which Zellweger syndrome (ZS) is the most severe. Although patients with ZS exhibit severe pathology in multiple organs such as the liver, kidney, brain, muscle, and bone, the pathogenesis remains largely unknown. Recent findings indicate that peroxisomes regulate intrinsic apoptotic pathways and upstream fission-fusion processes, disruption of which causes multiple organ dysfunctions reminiscent of ZS. In this review, we summarize recent findings about peroxisome-mediated regulation of mitochondrial morphology and its possible relationship with the pathogenesis of ZS.

Control of mitochondrial dynamics and apoptotic pathways by peroxisomes

Both peroxisomes and lipid droplets regulate cellular lipid homeostasis. Direct inter-organellar contacts as well as novel roles for proteins associated with peroxisome or lipid droplets occur when cells are induced to liberate fatty acids from lipid droplets. We have shown a non-canonical role for as subset of peroxisome-assembly (Peroxin) proteins in this process. Transmembrane proteins Peroxin3, Peroxin13 and Peroxin14 surround newly formed lipid droplets. Trafficking of Peroxin14 to lipid droplets was enhanced by loss of Peroxin19, which directs insertion of transmembrane proteins like Peroxin14 into the peroxisome bilayer membrane. Accumulation of Peroxin14 around lipid droplets did not induce changes to peroxisome size or number, nor was co-recruitment of the remaining Peroxins needed to assemble peroxisomes observed. Increasing the relative level of Peroxin14 surrounding lipid droplets affected recruitment of Hsl lipase. Fat-body specific reduction of these lipid droplet-associated Peroxins causes a unique effect on larval fat body development and affected their survival on lipid-enriched or minimal diets.

Recruitment of Peroxin14 to lipid droplets affects lipid storage in Drosophila.

Localized translation of peroxisomal membrane proteins is crucial for cellular functions.

https://www.science.org/doi/pdf/10.1126/sciadv.abk2141?download=true

Peroxisome function relies on organelle-associated mRNA translation

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Peroxisome function relies on organelle-associated mRNA translation