bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023‒02‒26
nine papers selected by
Verena Kohler
  1. Seipin-still a mysterious protein?
  2. Mitochondrial membrane biogenesis: A new pathway for lipid transport mediated by PERK/E-Syt1 complex.
  3. PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration.
  4. Structural organization of RDGB (retinal degeneration B), a multi-domain lipid transfer protein: a molecular modelling and simulation based approach.
  5. Comparison among Neuroblastoma Stages Suggests the Involvement of Mitochondria in Tumor Progression.
  6. Crosstalk between Mfn2-mediated mitochondria associated membranes disorder and autophagy induced by molybdenum and cadmium in sheep heart.
  7. Ubiquitin and its relatives as wizards of the endolysosomal system.
  8. Adenosine monophosphate deaminase in the endoplasmic reticulum-mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts.
  9. Mitochondrial cristae in health and disease.
  1. Front Cell Dev Biol. 2023 ;11 1112954
    Seipin-still a mysterious protein?
    Veijo T Salo.
      Cells store excess energy in the form of lipid droplets (LDs), a specialized sub-compartment of the endoplasmic reticulum (ER) network. The lipodystrophy protein seipin is a key player in LD biogenesis and ER-LD contact site maintenance. Recent structural and in silico studies have started to shed light on the molecular function of seipin as a LD nucleator in early LD biogenesis, whilst new cell biological work implies a role for seipin in ER-mitochondria contact sites and calcium metabolism. In this minireview, I discuss recent insights into the molecular function of seipin.
    Keywords:  endoplasmic reticulum; lipid droplet; lipid droplet-ER contact sites; membrane contact site; mitochondria-ER contact sites; seipin
    DOI:  https://doi.org/10.3389/fcell.2023.1112954
  2. J Cell Biol. 2023 Mar 06. pii: e202301132. [Epub ahead of print]222(3):
    Mitochondrial membrane biogenesis: A new pathway for lipid transport mediated by PERK/E-Syt1 complex.
    Sébastien Leterme, Morgane Michaud.
      Despite decades of extensive research, mitochondrial lipid transport is a process far from fully understood. In this issue, Sassano et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202206008) identified a new complex, composed of E-Syt1 and PERK, which mediates lipid transport at ER-mitochondria contact sites and regulates mitochondrial functions in human cells.
    DOI:  https://doi.org/10.1083/jcb.202301132
  3. J Cell Biol. 2023 Mar 06. pii: e202206008. [Epub ahead of print]222(3):
    PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration.
    Maria Livia Sassano, Alexander R van Vliet, Ellen Vervoort, Sofie Van Eygen, Chris Van den Haute, Benjamin Pavie, Joris Roels, Johannes V Swinnen, Marco Spinazzi, Leen Moens, Kristina Casteels, Isabelle Meyts, Paolo Pinton, Saverio Marchi, Leila Rochin, Francesca Giordano, Blanca Felipe-Abrio, Patrizia Agostinis.
      The integrity of ER-mitochondria appositions ensures transfer of ions and phospholipids (PLs) between these organelles and exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the ER-mitochondria contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but the molecular effectors governing this process remain ill-defined. Here, we report that PERK promotes lipid trafficking at the ER-mitochondria contact sites (EMCS) through a non-conventional, unfolded protein response-independent, mechanism. PERK operates as an adaptor for the recruitment of the ER-plasma membrane tether and lipid transfer protein (LTP) Extended-Synaptotagmin 1 (E-Syt1), within the EMCS. In resting cells, the heterotypic E-Syt1-PERK interaction endorses transfer of PLs between the ER and mitochondria. Weakening the E-Syt1-PERK interaction or removing the lipid transfer SMP-domain of E-Syt1, compromises mitochondrial respiration. Our findings unravel E-Syt1 as a PERK interacting LTP and molecular component of the lipid trafficking machinery of the EMCS, which critically maintains mitochondrial homeostasis and fitness.
    DOI:  https://doi.org/10.1083/jcb.202206008
  4. J Biomol Struct Dyn. 2023 Feb 20. 1-15
    Structural organization of RDGB (retinal degeneration B), a multi-domain lipid transfer protein: a molecular modelling and simulation based approach.
    Harini Krishnan, Bishal Basak, Vaisaly R Nath, Shirish Mishra, Padinjat Raghu.
      Lipid transfer proteins (LTPs) that shuttle lipids at membrane contact sites (MCS) play an important role in maintaining cellular homeostasis. One such important LTP is the Retinal Degeneration B (RDGB) protein. RDGB is localized at the MCS formed between the endoplasmic reticulum (ER) and the apical plasma membrane (PM) in Drosophila photoreceptors where it transfers phosphatidylinositol (PI) during G-protein coupled phospholipase C signalling. Previously, the C-terminal domains of RDGB have been shown to be essential for its function and accurate localization. In this study, using in-silico integrative modelling we predict the structure of entire RDGB protein in complex with the ER membrane protein VAP. The structure of RDGB has then been used to decipher the structural features of the protein important for its orientation at the contact site. Using this structure, we identify two lysine residues in the C-terminal helix of the LNS2 domain important for interaction with the PM. Using molecular docking, we also identify an unstructured region USR1, immediately c-terminal to the PITP domain that is important for the interaction of RDGB with VAP. Overall the 10.06 nm length of the predicted RDGB-VAP complex spans the distance between the PM and ER and is consistent with the cytoplasmic gap between the ER and PM measured by transmission electron microscopy in photoreceptors. Overall our model explains the topology of the RDGB-VAP complex at this ER-PM contact site and paves the way for analysis of lipid transfer function in this setting.Communicated by Ramaswamy H. Sarma.
    Keywords:  Multidomain protein; lipid transfer protein; membrane contact sites; molecular dynamics simulation
    DOI:  https://doi.org/10.1080/07391102.2023.2179545
  5. Biomedicines. 2023 Feb 17. pii: 596. [Epub ahead of print]11(2):
    Comparison among Neuroblastoma Stages Suggests the Involvement of Mitochondria in Tumor Progression.
    Stefano Cagnin, Tomas Knedlik, Caterina Vianello, Ana Paula Magalhães Rebelo, Agnese De Mario, Marta Giacomello.
      Neuroblastoma (NB) is the most common extracranial tumor of early childhood and accounts for 15% of all pediatric cancer mortalities. However, the precise pathways and genes underlying its progression are unknown. Therefore, we performed a differential gene expression analysis of neuroblastoma stage 1 and stage 4 + 4S to discover biological processes associated with NB progression. From this preliminary analysis, we found that NB samples (stage 4 + 4S) are characterized by altered expression of some proteins involved in mitochondria function and mitochondria-ER contact sites (MERCS). Although further analyses remain necessary, this review may provide new hints to better understand NB molecular etiopathogenesis, by suggesting that MERCS alterations could be involved in the progression of NB.
    Keywords:  MAMs; MERCS; cancer; cytoskeleton; differentially expressed genes; endoplasmic reticulum; microtubules; mitochondria; mitochondria-associated membranes; mitochondrial dynamics; mitochondria–endoplasmic reticulum contact sites; neuroblastoma
    DOI:  https://doi.org/10.3390/biomedicines11020596
  6. Food Chem Toxicol. 2023 Feb 15. pii: S0278-6915(23)00062-5. [Epub ahead of print] 113660
    Crosstalk between Mfn2-mediated mitochondria associated membranes disorder and autophagy induced by molybdenum and cadmium in sheep heart.
    Chengcheng Peng, Shuqiu Yang, Fan Yang, Zhiwei Xiong, Qiang Liu, Shuxian Liao, Kai Huang, Wengen Wan, Huabin Cao.
      To investigate the crosstalk of mitochondria associated membranes (MAMs) disorder and autophagy co-induced by molybdenum (Mo) and cadmium (Cd) in sheep hearts. A total of 48 sheep were randomly divided into 4 groups: control group, Mo group, Cd group and Mo + Cd group. The intragastric administration lasted for 50 days. The results showed that Mo or/and Cd exposure could cause morphological damage, imbalance of trace elements and antioxidant function, Ca2+ concentration decreased markedly, and significantly increase the contents of Mo or/and Cd in myocardium. Additionally, the mRNA and protein levels of endoplasmic reticulum stress (ERS) related factors and mitochondrial biogenesis related factors were altered by Mo or/and Cd, as well as the content of ATP, inducing ERS and mitochondrial dysfunction. Meanwhile, Mo or/and Cd could lead to the alteration of expression level of MAMs-related genes and proteins, and the distance between mitochondria and endoplasmic reticulum (ER), resulting in MAMs disorder. Moreover, Mo or/and Cd exposure upregulated the mRNA and protein levels of autophagy related factors. In conclusion, our results revealed that Mo or/and Cd exposure caused ERS, mitochondrial dysfunction and structural MAMs disruption, ultimately leading to autophagy in sheep hearts, and the effects of Mo and Cd co-exposure were more obvious.
    Keywords:  Autophagy; Cadmium; Mitochondria associated membranes; Molybdenum
    DOI:  https://doi.org/10.1016/j.fct.2023.113660
  7. J Cell Sci. 2023 Feb 15. pii: jcs260101. [Epub ahead of print]136(4):
    Ubiquitin and its relatives as wizards of the endolysosomal system.
    Ilana Berlin, Aysegul Sapmaz, Virginie Stévenin, Jacques Neefjes.
      The endolysosomal system comprises a dynamic constellation of vesicles working together to sense and interpret environmental cues and facilitate homeostasis. Integrating extracellular information with the internal affairs of the cell requires endosomes and lysosomes to be proficient in decision-making: fusion or fission; recycling or degradation; fast transport or contacts with other organelles. To effectively discriminate between these options, the endolysosomal system employs complex regulatory strategies that crucially rely on reversible post-translational modifications (PTMs) with ubiquitin (Ub) and ubiquitin-like (Ubl) proteins. The cycle of conjugation, recognition and removal of different Ub- and Ubl-modified states informs cellular protein stability and behavior at spatial and temporal resolution and is thus well suited to finetune macromolecular complex assembly and function on endolysosomal membranes. Here, we discuss how ubiquitylation (also known as ubiquitination) and its biochemical relatives orchestrate endocytic traffic and designate cargo fate, influence membrane identity transitions and support formation of membrane contact sites (MCSs). Finally, we explore the opportunistic hijacking of Ub and Ubl modification cascades by intracellular bacteria that remodel host trafficking pathways to invade and prosper inside cells.
    Keywords:  Bacterial infection; Endosomes; Membrane contact sites; Membrane dynamics; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.260101
  8. J Diabetes Investig. 2023 Feb 23.
    Adenosine monophosphate deaminase in the endoplasmic reticulum-mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts.
    Arata Osanami, Tatsuya Sato, Yuki Toda, Masaki Shimizu, Atsushi Kuno, Hidemichi Kouzu, Toshiyuki Yano, Wataru Ohwada, Toshifumi Ogawa, Tetsuji Miura, Masaya Tanno.
      AIMS/INTRODUCTION: We previously showed that upregulation of myocardial adenosine monophosphate deaminase (AMPD) is associated with pressure overload-induced diastolic dysfunction in type 2 diabetes hearts. Here, we examined involvement of AMPD localized in the endoplasmic reticulum-mitochondria interface in mitochondrial Ca2+ overload and its pathological significance.MATERIALS AND METHODS: We used type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats (OLETF) and non-diabetes Long-Evans Tokushima Otsuka Fatty rats (LETO) as well as AMPD3-overexpressing H9c2 cells and human embryonic kidney 293 cells.
    RESULTS: OLETF, but not LETO, showed diastolic dysfunction under the condition of phenylephrine-induced pressure overload. The levels of 90-kDa AMPD3 in outer mitochondrial membranes/endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane (MAM) fractions were significantly higher in OLETF than in LETO. The area of the MAM quantified by electron microscopic analysis was 57% larger, mitochondrial Ca2+ level under the condition of pressure overload was 47% higher and Ca2+ retention capacity in MAM-containing crude mitochondria isolated before the pressure overloading was 21% lower in OLETF than in LETO (all P-values <0.05). Transfection of FLAG-AMPD3 in cells resulted in significant enlargement of the MAM area, and impairment in pyruvate/malate-driven adenosine triphosphate-stimulated and uncoupler-stimulated mitochondrial respiration compared with those in control cells.
    CONCLUSIONS: The findings suggest that 90-kDa AMPD3 localized in the endoplasmic reticulum-mitochondria interface promotes formation of the MAM, inducing mitochondrial Ca2+ overload and dysfunction in type 2 diabetes hearts.
    Keywords:  Adenosine monophosphate deaminase; Diabetic cardiomyopathy; Mitochondria-associated endoplasmic reticulum membrane
    DOI:  https://doi.org/10.1111/jdi.13982
  9. Int J Biol Macromol. 2023 Feb 20. pii: S0141-8130(23)00649-9. [Epub ahead of print] 123755
    Mitochondrial cristae in health and disease.
    Cheng Huang, Kun Deng, Minghua Wu.
      Mitochondria are centers of energy metabolism. The mitochondrial network is shaped by mitochondrial dynamics, including the processes of mitochondrial fission and fusion and cristae remodeling. The cristae folded by the inner mitochondrial membrane are sites of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, the factors and their coordinated interplay in cristae remodeling and linked human diseases have not been fully demonstrated. In this review, we focus on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase, which function in the dynamic remodeling of cristae. We summarized their contribution to sustaining functional cristae structure and abnormal cristae morphology, including a decreased number of cristae, enlarged cristae junctions, and cristae as concentric ring structures. These abnormalities directly impact cellular respiration and are caused by dysfunction or deletion of these regulators in diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy. Identifying the important regulators of cristae morphology and understanding their role in sustaining mitochondrial morphology could be applied to explore the pathologies of diseases and to develop relevant therapeutic tools.
    Keywords:  ATP synthase; Cristae ultrastructure; MICOS; MICU1; Mitochondria; OPA1
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123755
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