bims-mecosi Biomed News
on Membrane contact sites
Issue of 2024–12–01
eight papers selected by
Verena Kohler, Umeå University
  1. Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.
  2. Dynamic remodelling of the endoplasmic reticulum for mitosis.
  3. The ultrastructural and proteomic analysis of mitochondria-associated endoplasmic reticulum membrane in the midbrain of a Parkinson's disease mouse model.
  4. The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.
  5. Analysis of dopaminergic neuron-specific mitochondrial morphology and function using tyrosine hydroxylase reporter iPSC lines.
  6. ACSL4-mediated ZIP7-VDAC3 interaction regulates endoplasmic reticulum-mitochondria iron transfer in hepatocytes under PFOS exposure.
  7. Diacylglycerol metabolism and homeostasis in fungal physiology.
  8. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
  1. Neural Regen Res. 2024 Nov 13.
    Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.
    Yichen Peng, Li Zhou, Yaju Jin, Danli Wu, Na Chen, Chengcai Zhang, Hongpeng Liu, Chunlan Li, Rong Ning, Xichen Yang, Qiuyue Mao, Jiaxin Liu, Pengyue Zhang.
      The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca2+ signaling. Conversely, Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00630
  2. J Cell Sci. 2024 Nov 15. pii: jcs261444. [Epub ahead of print]137(22):
    Dynamic remodelling of the endoplasmic reticulum for mitosis.
    Suzan Kors, Anne-Lore Schlaitz.
      The endoplasmic reticulum (ER) is a dynamic and continuous membrane network with roles in many cellular processes. The importance and maintenance of ER structure and function have been extensively studied in interphase cells, yet recent findings also indicate crucial roles of the ER in mitosis. During mitosis, the ER is remodelled significantly with respect to composition and morphology but persists as a continuous network. The ER interacts with microtubules, actin and intermediate filaments, and concomitant with the mitotic restructuring of all cytoskeletal systems, ER dynamics and distribution change. The ER is a metabolic hub and several examples of altered ER functions during mitosis have been described. However, we lack an overall understanding of the ER metabolic pathways and functions that are active during mitosis. In this Review, we will discuss mitotic changes to the ER at different organizational levels to explore how the mitotic ER, with its distinct properties, might support cell division.
    Keywords:  Cell division; ER; ER dynamics and morphology; ER–cytoskeleton contacts; Endoplasmic reticulum; Membrane contact sites; Mitosis
    DOI:  https://doi.org/10.1242/jcs.261444
  3. Aging Cell. 2024 Nov 29. e14436
    The ultrastructural and proteomic analysis of mitochondria-associated endoplasmic reticulum membrane in the midbrain of a Parkinson's disease mouse model.
    Jin Liu, Yi Liu, Chao Gao, Hong Pan, Pei Huang, Yuyan Tan, Shengdi Chen.
      Recent studies indicated that the dysregulation of mitochondria-associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. In MPTP-treated mice, transmission electron microscopy was applied for MAM ultrastructural visualization. Nano ultra-high performance liquid chromatography-tandem mass spectrum and bioinformatic analysis were adopted to obtain underlying molecular data of MAM fractions. The loosened, shortened and reduced MAM tethering was found in substantia nigral neurons from MPTP-treated mice. In midbrain MAM proteomics, 158 differentially expressed proteins (DEPs) were identified between two groups. Specific DEPs were validated by western blot and exhibited significantly statistical changes, aligning with proteomic results. Bioinformatic analysis indicated that membrane, cytoplasm and cell projection were three major localizations for DEPs. Biological processes including metabolism, lipid transport, and immunological and apoptotic signaling pathways were greatly affected. For consensus MAM proteins, the enriched pathway analysis revealed the potential relationship between neurodegenerative diseases and MAM. Several biological processes such as peroxisome function and clathrin-mediated endocytosis, were clustered, which provided additional insights into the fundamental molecular pathways associated with MAM. In our study, we demonstrated disrupted ER-mitochondria contacts in an MPTP-induced PD mouse model. The underlying signatures of MAM were revealed by proteomics and bioinformatic analysis, providing valuable insights into its potential role in PD pathogenesis.
    Keywords:  1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine; Parkinson's disease; mitochondria‐associated endoplasmic reticulum membrane; proteomics; ultrastructure
    DOI:  https://doi.org/10.1111/acel.14436
  4. bioRxiv. 2024 Nov 11. pii: 2024.11.11.622945. [Epub ahead of print]
    The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.
    J Montesinos, K Kabra, M Uceda, D Larrea, R R Agrawal, K A Tamucci, M Pera, A C Ferre, N Gomez-Lopez, T D Yun, K R Velasco, E A Schon, E Area-Gomez.
      Cellular demands for cholesterol are met by a balance between its biosynthesis in the endoplasmic reticulum (ER) and its uptake from lipoproteins. Cholesterol levels in intracellular membranes form a gradient maintained by a complex network of mechanisms including the control of the expression, compartmentalization and allosteric modulation of the enzymes that balance endogenous and exogenous sources of cholesterol. Low-density lipoproteins (LDLs) are internalized and delivered to lysosomal compartments to release their cholesterol content, which is then distributed within cellular membranes. High-density lipoproteins (HDLs), on the other hand, can transfer their cholesterol content directly into cellular membranes through the action of receptors such as the scavenger receptor B type 1 (SR-B1; gene SCARB1 ). We show here that SR-B1-mediated exogenous cholesterol internalization from HDL stimulates the formation of lipid-raft subdomains in the ER known as mitochondria-associated ER membranes (MAM), that, in turn, suppress de novo cholesterol biosynthesis machinery. We propose that MAM is a regulatory hub for cholesterol homeostasis that offers a novel dimension for understanding the intracellular regulation of this important lipid.
    DOI:  https://doi.org/10.1101/2024.11.11.622945
  5. Anat Sci Int. 2024 Nov 29.
    Analysis of dopaminergic neuron-specific mitochondrial morphology and function using tyrosine hydroxylase reporter iPSC lines.
    Mutsumi Yokota.
      Changes in mitochondrial function and morphology contribute to the development of many neurological diseases. Parkinson's disease is one of the neurodegenerative diseases suspected to be associated with defects in mitochondrial function and quality control. The loss of dopaminergic neurons in the substantia nigra pars compacta is a well-known pathological feature of Parkinson's disease. It is important for elucidating the pathogenesis of Parkinson's disease to analyze mitochondrial function and morphology specific to dopaminergic neurons using live-cell imaging or electron microscopy. However, the cells differentiated into dopaminergic neurons from induced pluripotent stem cells generally comprise heterogeneous populations. We generated tyrosine hydroxylase (TH) reporter iPSC lines to distinguish dopaminergic neurons from other cells for live-cell imaging and electron microscopy. This review summarizes previous studies utilizing the TH reporter iPSC lines and discusses the importance of studying mitochondria specific to dopaminergic neurons. Additionally, it provides overviews of recent studies reporting changes in endoplasmic reticulum-mitochondrial contact sites in Parkinson's disease models.
    Keywords:  Dopaminergic neurons; Electron microscopy; Mitochondria; Parkinson’s disease; Tyrosine hydroxylase reporter iPSC
    DOI:  https://doi.org/10.1007/s12565-024-00816-z
  6. Sci Total Environ. 2024 Nov 25. pii: S0048-9697(24)07836-7. [Epub ahead of print]957 177679
    ACSL4-mediated ZIP7-VDAC3 interaction regulates endoplasmic reticulum-mitochondria iron transfer in hepatocytes under PFOS exposure.
    Peiyao Liang, Kefan Tian, Wei Yang, Ruzhen Feng, Yu Li, Lingli Hu, Kejing Wang, Tianming Qiu, Jingyuan Zhang, Xiance Sun, Xiaofeng Yao.
      Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant with adverse health consequences. Our previous studies showed that PFOS caused an increase in mitochondrial iron and accelerated the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), one classic executor in the ferroptosis pathway. As ACSL4 is located in the mitochondria-associated endoplasmic reticulum (ER) membranes, here, we intended to further explore the role of ACSL4 in the inter-organelle iron crosstalk between ER and mitochondria under PFOS exposure. We found that PFOS caused ER iron accumulation in mice liver and human hepatocytes L-02. Inhibition of solute carrier family 39 member 7 (SLC39A7/ZIP7), a potential ER iron efflux channel supposed by us, alleviated PFOS-induced mitochondrial iron overload and further elevated ER iron level. Knockdown of voltage-dependent anion channel 3 (VDAC3) or mitochondrial calcium uniporter (MCU), the respective potential mitochondrial iron influx channels in outer/inner mitochondrial membrane, reversed the mitochondrial iron overload and aggravated ER iron accumulation in the cells under PFOS treatment. ACSL4 interacted with both ZIP7 and VDAC3 in mice liver and L-02 cells after treatment with PFOS. Upon inhibition of ACSL4, the ZIP7-VDAC3 interaction was reduced, mitigating mitochondrial iron overload and exacerbating iron accumulation in ER. Inhibiting VDAC3 or ZIP7 reversed the overloaded cytosolic iron under PFOS treatment, however, we found no further decrease in cytosolic iron after simultaneous inhibiting VDAC3 and ZIP7 compared with respectively inhibiting VDAC3 or ZIP7 alone. Our study provides evidence and reveals the molecular mechanism underneath the ER-mitochondria iron crosstalk under PFOS exposure, providing new insights into and enriches the understanding of the iron network-regulating function of the ferroptosis executor ACSL4 and highlighting its role in PFOS toxicity.
    Keywords:  Acyl-CoA synthetase long-chain family member 4; Endoplasmic reticulum iron; Mitochondrial iron; Perfluorooctane sulfonate
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.177679
  7. FEMS Yeast Res. 2024 Nov 28. pii: foae036. [Epub ahead of print]
    Diacylglycerol metabolism and homeostasis in fungal physiology.
    Sudipta Mondal, Biswajit Pal, Rajan Sankaranarayanan.
      Diacylglycerol (DAG) is a relatively simple and primitive form of lipid, which does not possess a phospholipid headgroup. Being a central metabolite of the lipid metabolism network, DAGs are omnipresent in all life forms. While the role of DAG has been established in membrane and storage lipid biogenesis, it can impart crucial physiological functions including membrane shapeshifting, regulation of membrane protein activity and transduction of cellular signalling as a lipid-based secondary messenger. Besides, the chemical diversity of DAGs, due to fatty acyl chain composition, has been proposed to be the basis of its functional diversity. Therefore, cells must regulate DAG level at a spatio-temporal scale for homeostasis and adaptation. The vast network of eukaryotic lipid metabolism has been unravelled majorly by studying yeast models. Here, we review the current understanding and the emerging concepts in metabolic and functional aspects of DAG regulation in yeast. The implications can be extended to understand pathogenic fungi and mammalian counterparts as well as disease aetiology.
    Keywords:  Acyl-chain diversity; Diacylglycerol; Disco-interacting protein 2; Lipid metabolism; Lipid second messenger; Membrane contact site; Organelle membranes
    DOI:  https://doi.org/10.1093/femsyr/foae036
  8. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121
    ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
    Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.
      The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
    Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2410486121
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