bims-mecosi 2024-08-04 papers

Issue of 2024–08–04
six papers selected by
Verena Kohler, Umeå University

Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241261228

The Discovery of Mitochondria-Endoplasmic Reticulum Contact Sites (MERCs) as Mitochondria-Associated Membranes (MAMs).

Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options.

Keywords: endoplasmic reticulum; mitochondria; mutation; rare disease

DOI: https://doi.org/10.1177/25152564241261228

J Cell Biol. 2024 Sep 02. pii: e202407125. [Epub ahead of print]223(9):

A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.

York Posor, Volker Haucke.

Membrane contact sites (MCS) facilitate communication between organelles. Casler et al. (https://doi.org/10.1083/jcb.202308144) show that tripartite MCS between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM) regulate mitochondrial division and the distribution of phosphatidylinositol 4-phosphate [PI(4)P] on the PM.

DOI: https://doi.org/10.1083/jcb.202407125

Anal Chem. 2024 Jul 27.

3D Imaging of Lipid Droplet-Nuclear Membrane Contact Sites and Cirrhotic Lipid Droplet Overexpression.

Qingqing Ma, Ling Huang, Chenyuan Long, Weiying Lin.

To coordinate cellular physiology, cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites. Lipid droplets (LDs) and nuclear membrane (NM) contact sites are particularly vital communication hubs, playing key roles in the exchange of signaling molecules, lipids, and metabolites. However, there is still a lack of understanding of the specific morphology of the contact sites. Here, we combine advanced three-dimensional (3D) imaging with a high-brightness fluorescent probe specifically targeting LDs to map the structural landscape of LD-NM contact sites. The probe exhibits exceptional photophysical properties, making it highly suitable for visualizing the changes occurring in LDs during the apoptosis process. In addition, we utilize the advantages of the probe to accurately monitor the overexpression of abnormal LDs in cirrhosis by 3D imaging for the first time. The outcomes of this investigation highlight that the probe has potential as a robust imaging tool to investigate intricate biological functions of LDs and their implications in related diseases.

DOI: https://doi.org/10.1021/acs.analchem.4c03370

Curr Top Membr. 2024 Jun 24. pii: S1063-5823(24)00009-7. [Epub ahead of print]

How has the evolution of our understanding of the compartmentalization of sphingolipid biosynthesis over the past 30 years altered our view of the evolution of the pathway?

Assaf Biran, Tamir Dingjan, Anthony H Futerman.

Sphingolipids are unique among cellular lipids inasmuch as their biosynthesis is compartmentalized between the endoplasmic reticulum (ER) and the Golgi apparatus. This compartmentalization was first recognized about thirty years ago, and the current review not only updates studies on the compartmentalization of sphingolipid biosynthesis, but also discusses the ramifications of this feature for our understanding of how the pathway could have evolved. Thus, we augment some of our recent studies by inclusion of two further molecular pathways that need to be considered when analyzing the evolutionary requirements for generation of sphingolipids, namely contact sites between the ER and the Golgi apparatus, and the mechanism(s) of vesicular transport between these two organelles. Along with evolution of the individual enzymes of the pathway, their subcellular localization, and the supply of essential metabolites via the anteome, it becomes apparent that current models to describe evolution of the sphingolipid biosynthetic pathway may need substantial refinement.

Keywords: Ceramide; Contact site; Endoplasmic reticulum; Golgi apparatus; Sphingolipid; Vesicular transport

DOI: https://doi.org/10.1016/bs.ctm.2024.06.001

Comp Biochem Physiol C Toxicol Pharmacol. 2024 Jul 30. pii: S1532-0456(24)00157-1. [Epub ahead of print] 109989

Hesperidin alleviates terbuthylazine-induced ferroptosis via maintenance of mitochondria-associated endoplasmic reticulum membrane integrity in chicken hepatocytes.

Pan Guo, Quanwei Li, Shaofeng Wang, Xinyue Jiang, Qingwen Yang, Wenlan Yu, Khalid Awadh Al-Mutairi, Zhaoxin Tang, Qingyue Han, Jianzhao Liao.

Terbuthylazine (TBA) is a common triazine herbicide used in agricultural production, which causes toxic damage in multiple tissues. Hesperidin (HSP) is a flavonoid derivative that has anti-inflammatory, antioxidant and cytoprotective effects, but its role in reducing toxic damage caused by pesticides is still unclear. In this study, we aimed to investigate the toxic effect of TBA exposure on chicken hepatocytes and the therapeutic effect of HSP on the TBA-induced hepatotoxicity. Our results demonstrated that HSP could alleviate TBA exposure-induced endoplasmic reticulum (ER) stress. Interestingly, TBA significantly disrupted the integrity of mitochondria-associated endoplasmic reticulum membrane (MAM), while HSP treatment showed the opposite tendency. In addition, TBA could significantly trigger ferroptosis in liver, and HSP treatment reversed ferroptosis under TBA exposure. These results suggested that HSP could inhibit ER stress and alleviate ferroptosis under TBA exposure via maintaining MAM integrity, which provided a novel strategy to take precautions against TBA toxicity.

Keywords: ER stress; Ferroptosis; Hesperidin; MAM; Terbuthylazine; liver

DOI: https://doi.org/10.1016/j.cbpc.2024.109989

Diabetes Metab J. 2024 Jul 29.

PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca2+ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes.

Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang.

Background: Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods: High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca2+ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results: PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca2+ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion: PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca2+ into the mitochondria.

Keywords: Diabetes mellitus; Endoplasmic reticulum; Mitochondria; Pdzd8 protein, mouse

DOI: https://doi.org/10.4093/dmj.2023.0275