bims-mecosi 2023-12-03 papers

Issue of 2023–12–03
five papers selected by
Verena Kohler, Umeå University

Cell Calcium. 2023 Nov 19. pii: S0143-4160(23)00148-3. [Epub ahead of print]117 102837

Nanojunctions: Specificity of Ca2+ signaling requires nano-scale architecture of intracellular membrane contact sites.

Nicola Fameli, Cornelis van Breemen, Klaus Groschner.

Spatio-temporal definition of Ca2+ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion-reflecting confinement of the signalling unit, remains as yet elusive. Utilizing the Na+/Ca2+ Exchanger-1 / SR/ER Ca2+ ATPase-2-mediated ER Ca2+ refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture. Our stochastic modeling approach demonstrates that junctional ER Ca2+ refilling operates exclusively at nano-scale membrane spacing, with a strong inverse relationship between junctional width and signaling efficiency. Our model predicts a breakdown of junctional Ca2+ signaling with loss of reflecting membrane confinement. In addition we consider interactions between Ca2+ and the phospholipid membrane surface, which may support interfacial Ca2+ transport and promote receptor targeting. Alterations in the molecular and nano-scale membrane organization at organelle-PM contacts are suggested as a new concept in pathophysiology.

Keywords: Calcium signalling; Computational simulation; Na(+)/Ca(2+) exchanger; Nanojunctions; PM-ER junctions; Stochastic model

DOI: https://doi.org/10.1016/j.ceca.2023.102837

Cell Signal. 2023 Nov 23. pii: S0898-6568(23)00401-1. [Epub ahead of print]114 110986

The role of endoplasmic reticulum stress, mitochondrial dysfunction and their crosstalk in intervertebral disc degeneration.

Dengbo Yao, Enming Chen, Yuxi Li, Kun Wang, Zhuangyao Liao, Ming Li, Lin Huang.

Low back pain (LBP) is a pervasive global health issue. Roughly 40% of LBP cases are attributed to intervertebral disc degeneration (IVDD). While the underlying mechanisms of IVDD remain incompletely understood, it has been confirmed that apoptosis and extracellular matrix (ECM) degradation caused by many factors such as inflammation, oxidative stress, calcium (Ca2+) homeostasis imbalance leads to IVDD. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are involved in these processes. The initiation of ER stress precipitates cell apoptosis, and is also related to inflammation, levels of oxidative stress, and Ca2+ homeostasis. Additionally, mitochondrial dynamics, antioxidative systems, disruption of Ca2+ homeostasis are closely associated with Reactive Oxygen Species (ROS) and inflammation, promoting cell apoptosis. However, numerous crosstalk exists between the ER and mitochondria, where they interact through inflammatory cytokines, signaling pathways, ROS, or key molecules such as CHOP, forming positive and negative feedback loops. Furthermore, the contact sites between the ER and mitochondria, known as mitochondria-associated membranes (MAM), facilitate direct signal transduction such as Ca2+ transfer. However, the current attention towards this issue is insufficient. Therefore, this review summarizes the impacts of ER stress and mitochondrial dysfunction on IVDD, along with the possibly potential crosstalk between them, aiming to unveil novel avenues for IVDD intervention.

Keywords: Endoplasmic reticulum stress; Inflammation; Intervertebral disc degeneration; Mitochondria-associated membrane; Mitochondrial dysfunction; Oxidative stress

DOI: https://doi.org/10.1016/j.cellsig.2023.110986

Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231217867

Canonical and Non-Canonical Roles of SNX1 and SNX2 in Endosomal Membrane Dynamics.

Juliane Da Graça, Etienne Morel.

Sorting nexins (SNXs) are a family of membrane-binding proteins known to play a critical role in regulating endocytic pathway sorting and endosomal membrane trafficking. Among them, SNX1 and SNX2 are members of the SNX-BAR subfamily and possess a membrane-curvature domain and a phosphoinositide-binding domain, which enables their stabilization at the phosphatidylinositol-3-phosphate (PI3P)-positive surface of endosomes. While their binding to PI3P-positive platforms facilitates interaction with endosomal partners and stabilization at the endosomal membrane, their SNX-BAR region is pivotal for generating membrane tubulation from endosomal compartments. In this context, their primary identified biological roles-and their partnership-are tightly associated with the retromer and endosomal SNX-BAR sorting complex for promoting exit 1 complex trafficking, facilitating the transport of cargoes from early endosomes to the secretory pathway. However, recent literature indicates that these proteins also possess biological functions in other aspects of endosomal features and sorting processes. Notably, SNX2 has been found to regulate endosome-endoplasmic reticulum (ER) contact sites through its interaction with VAP proteins at the ER membrane. Furthermore, data from our laboratory show that SNX1 and SNX2 are involved in the tubulation of early endosomes toward ER sites associated with autophagy initiation during starvation. These findings shed light on a novel role of SNXs in inter-organelle tethering and communication. In this concise review, we will explore the non-retromer functions of SNX1 and SNX2, specifically focusing on their involvement in endosomal membrane dynamics during stress sensing and autophagy-associated processes.

Keywords: autophagy; endosomes; membrane dynamics; membrane tubulation; sorting nexins

DOI: https://doi.org/10.1177/25152564231217867

bioRxiv. 2023 Nov 18. pii: 2023.03.21.533722. [Epub ahead of print]

Proximity Proteome Analysis Reveals Novel TREM2 Interactors in the ER-Mitochondria Interface of Human Microglia.

Chulhwan Kwak, Gina M Finan, Yu Rim Park, Anjali Garg, Oscar Harari, Ji Young Mun, Hyun-Woo Rhee, Tae-Wan Kim.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in microglial biology and the pathogenesis of Alzheimer's disease (AD). Besides DNAX-activating protein 12 (DAP12), a communal adaptor for TREM2 and many other receptors, other cellular interactors of TREM2 remain largely elusive. We employed a 'proximity labeling' approach using a biotin ligase, TurboID, for mapping protein-protein interactions in live mammalian cells. We discovered novel TREM2-proximal proteins with diverse functions, including those localized to the Mitochondria-ER contact sites (MERCs), a dynamic subcellular 'hub' implicated in a number of crucial cell physiology such as lipid metabolism. TREM2 deficiency alters the thickness (inter-organelle distance) of MERCs, a structural parameter of metabolic state, in microglia derived from human induced pluripotent stem cells. Our TurboID-based TREM2 interactome study suggest novel roles for TREM2 in the structural plasticity of the MERCs, raising the possibility that dysregulation of MERC-related TREM2 functions contribute to AD pathobiology.

DOI: https://doi.org/10.1101/2023.03.21.533722

Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231211409

A Role for Two-Pore Channel Type 2 (TPC2)-Mediated Regulation of Membrane Contact Sites During Zebrafish Notochord Biogenesis?

Keira L Rice, Ching Man Chan, Jeffrey J Kelu, Andrew L Miller, Sarah E Webb.

We have previously shown that in the developing trunk of zebrafish embryos, two-pore channel type 2 (TPC2)-mediated Ca2+ release from endolysosomes plays a role in the formation of the skeletal slow muscle. In addition, TPC2-mediated Ca2+ signaling is required for axon extension and the establishment of synchronized activity in the primary motor neurons. Here, we report that TPC2 might also play a role in the development of the notochord of zebrafish embryos. For example, when tpcn2 was knocked down or out, increased numbers of small vacuoles were formed in the inner notochord cells, compared with the single large vacuole in the notochord of control embryos. This abnormal vacuolation was associated with embryos displaying attenuated body axis straightening. We also showed that TPC2 has a distinct pattern of localization in the notochord in embryos at ∼24 hpf. Finally, we conducted RNAseq to identify differentially expressed genes in tpcn2 mutants compared to wild-type controls, and found that those involved in actin filament severing, cellular component morphogenesis, Ca2+ binding, and structural constituent of cytoskeleton were downregulated in the mutants. Together, our data suggest that TPC2 activity plays a key role in notochord biogenesis in zebrafish embryos.

Keywords: endolysosomal vesicles; notochord development; tpcn2 mutants and morphants; trans-Ned19; two-pore channel type 2; zebrafish embryos

DOI: https://doi.org/10.1177/25152564231211409