Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes – the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.

All living organisms need to respond appropriately to changes in the extracellular milieu. Cellular mechanisms that enable such responses evolved in parallel with organismal complexity and intracellular Ca2+ signaling is one such mechanism where extracellular signals received at the cell membrane communicate with endoplasmic reticular stores of Ca2+, to stimulate appropriate Ca2+-mediated changes in cellular physiology. The amplitude and dynamics of endoplasmic reticulum (ER)-Ca2+ release in response to extracellular signals determines the nature of the cellular response. An understanding of how ER-Ca2+ channels might regulate cellular Ca2+ signaling in different cell types is lacking. In a recent paper, this question has been addressed in the context of neurons ( Chakraborty et al., 2023) and the implications of these new findings are discussed here.

Rapid increase in body surface area of growing zebrafish larvae (Danio rario) is partially accomplished by asynthetic fission of superficial epithelial cells (SECs) of the skin. There are two cycles of this atypical form of cell division which is unaccompanied by DNA replication; resulting in cells with a variable DNA content. Here, electron microscopy of basal epithelium cells that give rise to these SECs in zebrafish larvae shows aggregation of mitochondria around the nucleus and the formation of nucleus-mitochondria membrane contact sites. Membrane aggregates appear in the lumen of the nuclear envelope at these sites of membrane contact in some cells, suggesting lipid turnover in this vicinity. As the epithelial cells mature and stratify, the mitochondria are engulfed by extensions arising from the nuclear envelope. The mitochondrial outer membrane fragments and mitochondria fuse with the nuclear envelope and parts of the endoplasmic reticulum. Other organelles, including the Golgi apparatus, progressively localize to a central region of the cell and lose their integrity. Thus, asynthetic fission is accompanied by an atypical pattern of organelle destruction and a prelude to this is the formation of nucleus-mitochondria membrane contact sites.

The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.

Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca2+ homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca2+ transfer unit at ERMCS. These are often reported to form a Ca2+ funnel that fuels the mitochondrial low-affinity Ca2+ uptake system. We assess the available evidence on the IP3R subtype selectivity at the ERMCS and consider if IP3Rs have other roles at the ERMCS beyond providing Ca2+. Growing evidence suggests that all three IP3R subtypes can localise and regulate Ca2+ signalling at ERMCS. Furthermore, IP3Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca2+ at these sites. Evidence that various binding partners regulate the assembly and Ca2+ transfer at ERMCS populated by IP3R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca2+ microdomain that is required to fuel mitochondrial Ca2+ uptake.

In eukaryotic cells, lipid transfer can occur at membrane contact sites (MCS) to facilitate the exchange of various lipids between two adjacent cellular organelle membranes. Lipid transfer proteins (LTPs), including shuttle LTP or bridge-like LTP (BLTP), transport lipids at MCS and are critical for diverse cellular processes, including lipid metabolism, membrane trafficking, and cell signaling. BLTPs (BLTP1-5, including the ATG2 and VPS13 family proteins) contain lipid-accommodating hydrophobic repeating β-groove (RBG) domains that allow the bulk transfer of lipids through MCS. Compared with vesicular lipid transfer and shuttle LTP, BLTPs have been only recently identified. Their functions and regulatory mechanisms are currently being unraveled in various model organisms and by diverse approaches. In this review, we summarize the genetics, structural features, and biological functions of BLTP in the genetically tractable model organism C. elegans. We discuss our recent studies and findings on C. elegans LPD-3, a prototypical megaprotein ortholog of BLTP1, with identified lipid transfer functions that are evolutionarily conserved in multicellular organisms and in human cells. We also highlight areas for future research of BLTP using C. elegans and complementary model systems and approaches. Given the emerging links of BLTP to several human diseases, including Parkinson's disease and Alkuraya-Kučinskas syndrome, discovering evolutionarily conserved roles of BLTPs and their mechanisms of regulation and action should contribute to new advances in basic cell biology and potential therapeutic development for related human disorders.

Membrane contact sites (MCS) are critical for cellular functions of eukaryotes, as theyenable communication and exchange between organelles. Research over the last decadeunravelled the function and composition of MCS between a variety of organelles includingmitochondria, ER, plasma membrane, lysosomes, lipid droplets, peroxisome and endosome, toname a few. In fact, MCS are found between any pair of organelles studied to date, withcommon functions including lipid exchange, calcium signalling and organelle positioning inthe cell. Work in the past year has started addressing the composition and function ofnuclear-mitochondrial MCS. Tether components mediating these contacts in yeast have beenidentified via comprehensive phenotypic screens, which also revealed a possible linkbetween this contact and phosphatidylcholine metabolism. In human cells, and in theprotozoan parasites causing malaria, proximity between these organelles is proposed topromote cell survival via a mitochondrial retrograde response. These pioneering studiesshould inspire the field to explore what cellular processes depend on the exchange betweenthe nucleus and the mitochondrion, given that they play such central roles in cellbiology.

Recent studies indicated potential importance of membrane contact sites(MCS) between the endoplasmic reticulum (ER) and other cellularorganelles. These MCS have unique protein and lipid composition andserve as hubs for inter-organelle communication and signaling. Despiteextensive investigation of MCS protein composition and functionalroles, little is known about the process of MCS formation. In thisperspective, we propose a hypothesis that MCS are formed not as aresult of random interactions between membranes of ER and otherorganelles but on the basis of pre-existing cholesterol-enriched ERmicrodomains.