Coming together to define membrane contact sites

Scorrano, Luca; Matteis, Maria Antonietta De; Emr, Scott D.; Giordano, Francesca; Hajnóczky, György; Kornmann, Benoı̂t; Lackner, Laura L.; Levine, Tim P.; Pellegrini, Luca; Reinisch, Karin M; Meneghesso, Gaudenzio; Simmen, Thomas; Stenmark, Harald; Ungermann, Christian; Schuldiner, Maya

doi:10.1038/s41467-019-09253-3

Cited by 541 publications

(556 citation statements)

References 131 publications

Supporting

Mentioning

510

Contrasting

Unclassified

Order By: Relevance

“…Using electron microscopy 46 , we found no difference in the percentage of endosomes in close proximity (>30 nm) to ER between wild type and TMEM16K knockout cells (Supplemental Fig. 5a,b), consistent with the presence of multiple proteins maintaining these contacts 47,48 . We have further strengthened these observations with proximity ligation assay (PLA) in situ, a powerful novel approach to study contact sites alterations in a quantitative manner.…”

supporting

confidence: 57%

“TMEM16K is an interorganelle regulator of endosomal sorting”

Petković

Oses-Prieto

Burlingame

et al. 2020

Preprint

View full text Add to dashboard Cite

Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime 1 . The endolysosomal pathway plays a prominent role in this process by regulating protein and lipid sorting and degradation 2 . Here, we report that TMEM16K, an endoplasmic reticulum lipid scramblase 3 causative for spinocerebellar ataxia (SCAR10), is an interorganelle regulator of the endolysosomal pathway. We identify endosomal transport as a major functional cluster of TMEM16K in proximity biotinylation proteomics analyses. TMEM16K forms contact sites with endosomes, reconstituting split-GFP with small GTPase RAB7. Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites. Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10. Thus, TMEM16K-containing ER-endosome contact sites represent clinically relevant platforms for regulating endosomal sorting.Cellular organelles do not act as discrete autonomous units, but rather as interconnected hubs that engage in extensive communication to coordinate their function over a lifetime and maintain cell homeostasis. An emerging theme is that such coordination can be mediated via membrane contact sites (MCS) between distinct organelles. These MCS are specialized microdomains of close proximity between the organelles that modulate essential cellular processes like lipid homeostasis 4-6 and organelle biogenesis 7 . While multiple human orthologues of MCS proteins 8,9 have been linked with a broad range of age-related pathologies, the identity and functions of membrane contact sites in maintaining cellular physiology remain an open question.

show abstract

supporting

confidence: 57%

“TMEM16K is an interorganelle regulator of endosomal sorting”

Petković

Oses-Prieto

Burlingame

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The identification of structures allowing membrane tethering of two organelles into close proximity has instigated considerable research interest into the (patho)physiologic role of inter-organelle contact sites (reviewed in [79]). Indeed, the juxtaposition (<30nm) of membranes of identical (homotypic contacts) or distinct organelles/membrane types (heterotypic contacts) acts as a domain for inter-organelle communication [79].…”

Section: Nondegradative Pathwaysmentioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

View full text Add to dashboard Cite

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca 2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.Cells 2020, 9, 598 2 of 18 instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and stem cell exhaustion [3]. According to the geroscience hypothesis, perturbations in these mechanisms increase the susceptibility to most chronic diseases, functional loss, and eventually, death [4]. Hence, these biologic pillars represent ideal targets for interventions to foster healthy aging [5,6].Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play sensor-transducer-effector roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness [7,8]. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogene...

show abstract

“…A distance threshold ≤ 30 nm was chosen as representative of an interaction between nearby organelles, on the basis of previously established morphometric analysis in animal and plant cells (Helle et al, 2013;Mueller-Schuessele and Michaud, 2018;Scorrano et al, 2019). Red: original image.…”

Section: -Optimization Of Sample Preparation and Image Analysis Workfmentioning

confidence: 99%

In-cell quantitative structural imaging of phytoplankton using 3D electron microscopy

Uwizeye

Decelle

Jouneau

et al. 2020

Preprint

View full text Add to dashboard Cite

Phytoplankton is a minor fraction of the global biomass playing a major role in primary production and climate. Despite improved understanding of phytoplankton diversity and genomics, we lack nanoscale subcellular imaging approaches to understand their physiology and cell biology. Here, we present a complete Focused Ion Beam -Scanning Electron Microscopy (FIB-SEM) workflow (from sample preparation to image processing) to generate nanometric 3D phytoplankton models. Tomograms of entire cells, representatives of six ecologically-successful phytoplankton unicellular eukaryotes, were used for quantitative morphometric analysis. Besides lineage-specific cellular architectures, we observed common features related to cellular energy management: i) conserved cell-volume fractions occupied by the different organelles; ii) consistent plastid-mitochondria interactions, iii) constant volumetric ratios in these energy-producing organelles. We revealed detailed subcellular features related to chromatin organization and to biomineralization. Overall, this approach opens new perspectives to study phytoplankton acclimation responses to abiotic and biotic factors at a relevant biological scale.

show abstract

Coming together to define membrane contact sites

Cited by 541 publications

References 131 publications

“TMEM16K is an interorganelle regulator of endosomal sorting”

“TMEM16K is an interorganelle regulator of endosomal sorting”

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

In-cell quantitative structural imaging of phytoplankton using 3D electron microscopy

Contact Info

Product

Resources

About