bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–06–16
seven papers selected by
Verena Kohler, Umeå University
  1. IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.
  2. Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.
  3. Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
  4. Partitioning into ER membrane microdomains impacts autophagic protein turnover during cellular aging.
  5. Mitochondrial membrane synthesis, remodelling and cellular trafficking.
  6. The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after mitosis.
  7. Correction to: Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.
  1. Exp Eye Res. 2024 Jun 06. pii: S0014-4835(24)00186-6. [Epub ahead of print]245 109965
    IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.
    Li Xu, Yihua Xu, Yaoxu Jiang, Jingjing Jiang, Shimei Chen, Dandan Sun, Shenping Li, Fang Wei, Hong Zhu.
      Mitochondria-associated ER membranes (MAMs) are contact sites that enable bidirectional communication between the ER (endoplasmic reticulum) and mitochondria, including the transfer of Ca2+ signals. MAMs are essential for mitochondrial function and cellular energy metabolism. However, unrestrained Ca2+ transfer to the mitochondria can lead to mitochondria-dependent apoptosis. IP3R2 (Inositol 1,4,5-trisphosphate receptor 2) is an important intracellular Ca2+ channel. This study investigated the contribution of IP3R2-MAMs to hypoxia-induced apoptosis in photoreceptor cells. A photoreceptor hypoxia model was established by subretinal injection of hyaluronic acid (1%) in C57BL/6 mice and 1% O2 treatment in 661W cells. Transmission electron microscopy (TEM), ER-mitochondria colocalization, and the MAM reporter were utilized to evaluate MAM alterations. Cell apoptosis and mitochondrial homeostasis were evaluated using immunofluorescence (IF), flow cytometry, western blotting (WB), and ATP assays. SiRNA transfection was employed to silence IP3R2 in 661W cells. Upon hypoxia induction, MAMs were significantly increased in photoreceptors both in vivo and in vitro. This was accompanied by the activation of mitochondrial apoptosis and disruption of mitochondrial homeostasis. Elevated MAM-enriched IP3R2 protein levels induced by hypoxic injury led to mitochondrial calcium overload and subsequent photoreceptor apoptosis. Notably, IP3R2 knockdown not only improved mitochondrial morphology but also restored mitochondrial function in photoreceptors by limiting MAM formation and thereby attenuating mitochondrial calcium overload under hypoxia. Our results suggest that IP3R2-MAM-mediated mitochondrial calcium overload plays a critical role in mitochondrial dyshomeostasis, ultimately contributing to photoreceptor cell death. Targeting MAM constitutive proteins might provide an option for a therapeutic approach to mitigate photoreceptor death in retinal detachment.
    Keywords:  Hypoxia; IP3R2; Mitochondria; Mitochondria-associated endoplasmic reticulum membranes (MAM); Photoreceptor
    DOI:  https://doi.org/10.1016/j.exer.2024.109965
  2. J Transl Med. 2024 Jun 09. 22(1): 552
    Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.
    Esther Densu Agyapong, Gaia Pedriali, Daniela Ramaccini, Esmaa Bouhamida, Elena Tremoli, Carlotta Giorgi, Paolo Pinton, Giampaolo Morciano.
      Acute myocardial infarction (AMI) is a serious condition that occurs when part of the heart is subjected to ischemia episodes, following partial or complete occlusion of the epicardial coronary arteries. The resulting damage to heart muscle cells have a significant impact on patient's health and quality of life. About that, recent research focused on the role of the sarcoplasmic reticulum (SR) and mitochondria in the physiopathology of AMI. Moreover, SR and mitochondria get in touch each other through multiple membrane contact sites giving rise to the subcellular region called mitochondria-associated membranes (MAMs). MAMs are essential for, but not limited to, bioenergetics and cell fate. Disruption of the architecture of these regions occurs during AMI although it is still unclear the cause-consequence connection and a complete overview of the pathological changes; for sure this concurs to further damage to heart muscle. The calcium ion (Ca2+) plays a pivotal role in the pathophysiology of AMI and its dynamic signaling between the SR and mitochondria holds significant importance. In this review, we tried to summarize and update the knowledge about the roles of these organelles in AMI from a Ca2+ signaling point of view. Accordingly, we also reported some possible cardioprotective targets which are directly or indirectly related at limiting the dysfunctions caused by the deregulation of the Ca2+ signaling.
    DOI:  https://doi.org/10.1186/s12967-024-05240-5
  3. Cell Death Dis. 2024 Jun 10. 15(6): 405
    Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
    Patricia Morcillo, Khushbu Kabra, Kevin Velasco, Hector Cordero, Sarah Jennings, Taekyung D Yun, Delfina Larrea, H Orhan Akman, Eric A Schon.
      Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
    DOI:  https://doi.org/10.1038/s41419-024-06781-9
  4. Sci Rep. 2024 06 13. 14(1): 13653
    Partitioning into ER membrane microdomains impacts autophagic protein turnover during cellular aging.
    Simon Prokisch, Sabrina Büttner.
      Eukaryotic membranes are compartmentalized into distinct micro- and nanodomains that rearrange dynamically in response to external and internal cues. This lateral heterogeneity of the lipid bilayer and associated clustering of distinct membrane proteins contribute to the spatial organization of numerous cellular processes. Here, we show that membrane microdomains within the endoplasmic reticulum (ER) of yeast cells are reorganized during metabolic reprogramming and aging. Using biosensors with varying transmembrane domain length to map lipid bilayer thickness, we demonstrate that in young cells, microdomains of increased thickness mainly exist within the nuclear ER, while progressing cellular age drives the formation of numerous microdomains specifically in the cortical ER. Partitioning of biosensors with long transmembrane domains into these microdomains increased protein stability and prevented autophagic removal. In contrast, reporters with short transmembrane domains progressively accumulated at the membrane contact site between the nuclear ER and the vacuole, the so-called nucleus-vacuole junction (NVJ), and were subjected to turnover via selective microautophagy occurring specifically at these sites. Reporters with long transmembrane domains were excluded from the NVJ. Our data reveal age-dependent rearrangement of the lateral organization of the ER and establish transmembrane domain length as a determinant of membrane contact site localization and autophagic degradation.
    DOI:  https://doi.org/10.1038/s41598-024-64493-8
  5. J Inherit Metab Dis. 2024 Jun 14.
    Mitochondrial membrane synthesis, remodelling and cellular trafficking.
    Martina Messina, Frédéric M Vaz, Shamima Rahman.
      Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.
    Keywords:  MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/jimd.12766
  6. EMBO Rep. 2024 Jun 14.
    The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after mitosis.
    Helena Bragulat-Teixidor, Keisuke Ishihara, Gréta Martina Szücs, Shotaro Otsuka.
      Junctions between the endoplasmic reticulum (ER) and the outer membrane of the nuclear envelope (NE) physically connect both organelles. These ER-NE junctions are essential for supplying the NE with lipids and proteins synthesized in the ER. However, little is known about the structure of these ER-NE junctions. Here, we systematically study the ultrastructure of ER-NE junctions in cryo-fixed mammalian cells staged in anaphase, telophase, and interphase by correlating live cell imaging with three-dimensional electron microscopy. Our results show that ER-NE junctions in interphase cells have a pronounced hourglass shape with a constricted neck of 7-20 nm width. This morphology is significantly distinct from that of junctions within the ER network, and their morphology emerges as early as telophase. The highly constricted ER-NE junctions are seen in several mammalian cell types, but not in budding yeast. We speculate that the unique and highly constricted ER-NE junctions are regulated via novel mechanisms that contribute to ER-to-NE lipid and protein traffic in higher eukaryotes.
    Keywords:  Correlative Light-electron Microscopy; Endoplasmic Reticulum; Membrane Contact Site; Nuclear Envelope; Open Mitosis
    DOI:  https://doi.org/10.1038/s44319-024-00175-w
  7. Acta Neuropathol. 2024 Jun 13. 147(1): 99
    Correction to: Disruption of MAM integrity in mutant FUS oligodendroglial progenitors from hiPSCs.
    Yingli Zhu, Thibaut Burg, Katrien Neyrinck, Tim Vervliet, Fatemeharefeh Nami, Ellen Vervoort, Karan Ahuja, Maria Livia Sassano, Yoke Chin Chai, Arun Kumar Tharkeshwar, Jonathan De Smedt, Haibo Hu, Geert Bultynck, Patrizia Agostinis, Johannes V Swinnen, Ludo Van Den Bosch, Rodrigo Furtado Madeiro da Costa, Catherine Verfaillie.
      
    DOI:  https://doi.org/10.1007/s00401-024-02748-4
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