bims-mecosi 2024-01-21 papers

Issue of 2024‒01‒21
four papers selected by
Verena Kohler, Umeå University

Cell. 2024 Jan 18. pii: S0092-8674(23)01328-4. [Epub ahead of print]187(2): 257-270

Making the connection: How membrane contact sites have changed our view of organelle biology.

G K Voeltz, E M Sawyer, G Hajnóczky, W A Prinz.

The view of organelles and how they operate together has changed dramatically over the last two decades. The textbook view of organelles was that they operated largely independently and were connected by vesicular trafficking and the diffusion of signals through the cytoplasm. We now know that all organelles make functional close contacts with one another, often called membrane contact sites. The study of these sites has moved to center stage in cell biology as it has become clear that they play critical roles in healthy and developing cells and during cell stress and disease states. Contact sites have important roles in intracellular signaling, lipid metabolism, motor-protein-mediated membrane dynamics, organelle division, and organelle biogenesis. Here, we summarize the major conceptual changes that have occurred in cell biology as we have come to appreciate how contact sites integrate the activities of organelles.

DOI: https://doi.org/10.1016/j.cell.2023.11.040

Am J Physiol Gastrointest Liver Physiol. 2024 Jan 16.

Characterisation of Mitochondria-associated ER membranes in the enteric nervous system under physiological and pathological conditions.

Giada Delfino, Jean Baptiste Briand, Thibauld Oullier, Léa Nienkemper, Jenny Greig, Joëlle Véziers, Michel Neunlist, Pascal Derkinderen, Sebastien Paillusson.

Alterations in endoplasmic reticulum-mitochondria associations and in mitochondria-associated ER membrane (MAM) behaviour have been reported in the brain in several neurodegenerative diseases. Despite the emerging role of the gut-brain axis in neurodegenerative disorders, the biology of MAM in the enteric nervous system (ENS) has not previously been studied. Therefore, we set out to characterise the MAM in the distal colon of wild type C57BL/6J mice and in senescence accelerated mouse prone 8 (SAMP8), a mouse model of age-related neurodegeneration. We showed for the first time that MAM are widely present in enteric neurons and that their association is altered in SAMP8 mice. We then examined the functions of MAM in a primary culture model of enteric neurons and showed that calcium homeostasis was altered in SAMP8 mice when compared to control animals. These findings provide the first detailed characterisation of MAM in the ENS under physiological conditions and during age-associated neurodegeneration. Further investigation of MAM modifications in the ENS in disease may provide valuable information about the possible role of enteric MAM in neurodegenerative diseases.

Keywords: Alzheimer's disease; Mitochondria associated ER membranes; Parkinson's disease; ageing; enteric nervous system

DOI: https://doi.org/10.1152/ajpgi.00224.2023

Cell Rep Methods. 2024 Jan 11. pii: S2667-2375(23)00378-8. [Epub ahead of print] 100692

Using MitER for 3D analysis of mitochondrial morphology and ER contacts.

Therese Kichuk, Satyen Dhamankar, Saurabh Malani, William A Hofstadter, Scott A Wegner, Ileana M Cristea, José L Avalos.

We have developed an open-source workflow that allows for quantitative single-cell analysis of organelle morphology, distribution, and inter-organelle contacts with an emphasis on the analysis of mitochondria and mitochondria-endoplasmic reticulum (mito-ER) contact sites. As the importance of inter-organelle contacts becomes more widely recognized, there is a concomitant increase in demand for tools to analyze subcellular architecture. Here, we describe a workflow we call MitER (pronounced "mightier"), which allows for automated calculation of organelle morphology, distribution, and inter-organelle contacts from 3D renderings by employing the animation software Blender. We then use MitER to quantify the variations in the mito-ER networks of Saccharomyces cerevisiae, revealing significantly more mito-ER contacts within respiring cells compared to fermenting cells. We then demonstrate how this workflow can be applied to mammalian systems and used to monitor mitochondrial dynamics and inter-organelle contact in time-lapse studies.

Keywords: CP: Imaging; Saccharomyces cerevisea; image analysis; imaging; inter-organelle contact; mitochondrial-ER contact; organelle distribution; organelle morphology

DOI: https://doi.org/10.1016/j.crmeth.2023.100692

Cell Rep. 2024 Jan 17. pii: S2211-1247(24)00009-3. [Epub ahead of print]43(2): 113681

Partial loss of MCU mitigates pathology in vivo across a diverse range of neurodegenerative disease models.

Madeleine J Twyning, Roberta Tufi, Thomas P Gleeson, Kinga M Kolodziej, Susanna Campesan, Ana Terriente-Felix, Lewis Collins, Federica De Lazzari, Flaviano Giorgini, Alexander J Whitworth.

Mitochondrial calcium (Ca2+) uptake augments metabolic processes and buffers cytosolic Ca2+ levels; however, excessive mitochondrial Ca2+ can cause cell death. Disrupted mitochondrial function and Ca2+ homeostasis are linked to numerous neurodegenerative diseases (NDs), but the impact of mitochondrial Ca2+ disruption is not well understood. Here, we show that Drosophila models of multiple NDs (Parkinson's, Huntington's, Alzheimer's, and frontotemporal dementia) reveal a consistent increase in neuronal mitochondrial Ca2+ levels, as well as reduced mitochondrial Ca2+ buffering capacity, associated with increased mitochondria-endoplasmic reticulum contact sites (MERCs). Importantly, loss of the mitochondrial Ca2+ uptake channel MCU or overexpression of the efflux channel NCLX robustly suppresses key pathological phenotypes across these ND models. Thus, mitochondrial Ca2+ imbalance is a common feature of diverse NDs in vivo and is an important contributor to the disease pathogenesis. The broad beneficial effects from partial loss of MCU across these models presents a common, druggable target for therapeutic intervention.

Keywords: Alzheimer's disease; CP: Neuroscience; Drosophila; Huntington's disease; MCU; NCLX; Parkinson's disease; calcium overload; frontotemporal dementia; mitochondrial calcium; neurodegeneration

DOI: https://doi.org/10.1016/j.celrep.2024.113681