bims-mecosi 2024-05-12 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2024‒05‒12
eight papers selected by
Verena Kohler, Umeå University

Mfn2 regulates mitochondria and mitochondria-associated endoplasmic reticulum membrane function in neurodegeneration induced by repeated sevoflurane exposure.
Omegasomes control formation, expansion, and closure of autophagosomes.
Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases.
Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-Mitochondria miscommunication in the liver of HFD mice.
Correlation between Mitochondria-Associated Endoplasmic Reticulum Membrane-Related Genes and Cellular Senescence-Related Genes in Osteoarthritis.
Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies.
Morphodynamical adaptation of the endolysosomal system to stress.
Temporal multiscale modeling of biochemical regulatory networks: Calcium-regulated hepatocyte lipid and glucose metabolism.

Exp Neurol. 2024 May 03. pii: S0014-4886(24)00133-X. [Epub ahead of print]377 114807

Mfn2 regulates mitochondria and mitochondria-associated endoplasmic reticulum membrane function in neurodegeneration induced by repeated sevoflurane exposure.

Ruilou Zhu, Lu Liu, Tian Mao, Xiaoling Wang, Yubao Li, Ting Li, Shuang Lv, Shuang Zeng, Ningning Fu, Ningning Li, Yangyang Wang, Mingyang Sun, Jiaqiang Zhang.

  Repeated sevoflurane exposure in neonatal mice can leads to neuronal apoptosis and mitochondrial dysfunction. The mitochondria are responsible for energy production to maintain homeostasis in the central nervous system. The mitochondria-associated endoplasmic reticulum membrane (MAM) is located between the mitochondria and endoplasmic reticulum (ER), and it is critical for mitochondrial function and cell survival. MAM malfunction contributes to neurodegeneration, however, whether it is involved in sevoflurane-induced neurotoxicity remains unknown. Our study demonstrated that repeated sevoflurane exposure induced mitochondrial dysfunction and dampened the MAM structure. The upregulated ER-mitochondria tethering enhanced Ca2+ transition from the cytosol to the mitochondria. Overload of mitochondrial Ca2+ contributed to opening of the mitochondrial permeability transition pore (mPTP), which caused neuronal apoptosis. Mitofusin 2(Mfn2), a key regulator of ER-mitochondria contacts, was found to be suppressed after repeated sevoflurane exposure, while restoration of Mfn2 expression alleviated cognitive dysfunction due to repeated sevoflurane exposure in the adult mice. These evidences suggest that sevoflurane-induced MAM malfunction is vulnerable to Mfn2 suppression, and the enhanced ER-mitochondria contacts promotes mitochondrial Ca2+ overload, contributing to mPTP opening and neuronal apoptosis. This paper sheds light on a novel mechanism of sevoflurane-induced neurotoxicity. Furthermore, targeting Mfn2-mediated regulation of the MAM structure and mitochondrial function may provide a therapeutic advantage in sevoflurane-induced neurodegeneration.

Keywords:  MAM; Mfn2; Mitochondrial Ca(2+) overload; Neurotoxicity; Sevoflurane

DOI:  https://doi.org/10.1016/j.expneurol.2024.114807
Bioessays. 2024 May 09. e2400038

Omegasomes control formation, expansion, and closure of autophagosomes.

Viola Nähse, Harald Stenmark, Kay O Schink.

  Autophagy, an essential cellular process for maintaining cellular homeostasis and eliminating harmful cytoplasmic objects, involves the de novo formation of double-membraned autophagosomes that engulf and degrade cellular debris, protein aggregates, damaged organelles, and pathogens. Central to this process is the phagophore, which forms from donor membranes rich in lipids synthesized at various cellular sites, including the endoplasmic reticulum (ER), which has emerged as a primary source. The ER-associated omegasomes, characterized by their distinctive omega-shaped structure and accumulation of phosphatidylinositol 3-phosphate (PI3P), play a pivotal role in autophagosome formation. Omegasomes are thought to serve as platforms for phagophore assembly by recruiting essential proteins such as DFCP1/ZFYVE1 and facilitating lipid transfer to expand the phagophore. Despite the critical importance of phagophore biogenesis, many aspects remain poorly understood, particularly the complete range of proteins involved in omegasome dynamics, and the detailed mechanisms of lipid transfer and membrane contact site formation.

Keywords:  DFCP1; FYVE domain; PI3P; omegasome; phagophore

DOI:  https://doi.org/10.1002/bies.202400038
Ageing Res Rev. 2024 May 06. pii: S1568-1637(24)00138-7. [Epub ahead of print]98 102320

Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases.

Tao Jiang, Nan Ruan, Pengcheng Luo, Qian Wang, Xiuxian Wei, Yi Li, Yue Dai, Li Lin, Jiagao Lv, Yu Liu, Cuntai Zhang.

  Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of age-related diseases, including neurodegenerative, cardiovascular, and metabolic diseases. Within the aging process, the morphology and function of mitochondria and the endoplasmic reticulum (ER) undergo alterations, particularly in the structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve as vital intracellular signaling hubs, facilitating communication between the ER and mitochondria when regulating various cellular events, including calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis. The formation of MAMs is partly dependent on the interaction between the vesicle-associated membrane protein-associated protein-B (VAPB) and protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun to elucidate the pivotal role of the VAPB-PTPIP51 tether in the initiation and progression of age-related diseases. In this study, we delineate the intricate structure and multifunctional role of the VAPB-PTPIP51 tether and discuss its profound implications in aging-associated diseases. Moreover, we provide a comprehensive overview of potential therapeutic interventions and pharmacological agents targeting the VAPB-PTPIP51-mediated MAMs, thereby offering a glimmer of hope in mitigating aging processes and treating age-related disorders.

Keywords:  Aging; Endoplasmic reticulum; MAMs; Mitochondria; PTPIP51; VAPB

DOI:  https://doi.org/10.1016/j.arr.2024.102320
Biomed Pharmacother. 2024 May 03. pii: S0753-3322(24)00566-3. [Epub ahead of print]175 116682

Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-Mitochondria miscommunication in the liver of HFD mice.

Yumeng Li, Xutong Tian, Qian Yu, Tongtong Bao, Chao Dai, Liang Jiang, Kaimin Niu, Jianying Yang, Shujin Wang, Xin Wu.

  The interaction between endoplasmic reticulum (ER) and mitochondria has been shown to play a key role in hepatic steatosis during chronic obesity. β-nicotinamide mononucleotide (NMN) has been reported to regulate obesity, however, its molecular mechanism at the subcellular level remains unclear. Here, NMN improved liver steatosis and insulin resistance in chronic high-fat diet (HFD) mice. RNA-seq showed that compared with the liver of HFD mice, NMN intervention enhanced fat digestion and absorption and stimulated the cholesterol metabolism signaling pathways, while impaired insulin resistance and the fatty acid biosynthesis signaling pathways. Mechanistically, NMN ameliorated mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) (P < 0.01) levels. This effect increased the contact sites (mitochondria-associated membranes [MAMs]) between ER and mitochondria, thereby promoting intracellular ATP (P < 0.05) production and mitigating lipid metabolic disturbances in the liver of HFD mice. Taken together, this study provided a theoretical basis for restoring metabolic dynamic equilibrium in the liver of HFD mice by increasing MAMs via the nutritional strategy of NMN supplementation.

Keywords:  Endoplasmic reticulum stress; HFD mice; Hepatic steatosis; Mitochondrial dysfunction; NMN

DOI:  https://doi.org/10.1016/j.biopha.2024.116682
ACS Omega. 2024 Apr 30. 9(17): 19169-19181

Correlation between Mitochondria-Associated Endoplasmic Reticulum Membrane-Related Genes and Cellular Senescence-Related Genes in Osteoarthritis.

Hui-Min Li, Chenhuan Wang, Qixue Liu, Zhicheng Tong, Binghua Song, Wei Wei, Chong Teng.

BACKGROUND: The role of mitochondria-associated endoplasmic reticulum membrane (MAM) formation in the development of osteoarthritis (OA) is yet unclear.METHODS: A mix of bioinformatics methods and in vitro experimental methodologies was used to study and corroborate the role of MAM-related genes and cellular senescence-related genes in the development of OA. The Gene Expression Omnibus database was used to obtain the microarray information that is relevant to the OA. Several bioinformatic methods were employed to carry out function enrichment analysis and protein-protein correlation analysis, build the correlation regulatory network, and investigate potential relationships between MAM-related genes and cellular senescence-related genes in OA. These methods also served to identify the MAM-related and OA-related genes (MAM-OARGs).
RESULTS: For the additional functional enrichment analysis, a total of 13 MAM-OARGs were detected. The correlation regulatory network was also created. Hub MAM-OARGs were shown to have a strong correlation with genes relevant to cellular senescence in OA. Results of in vitro experiments further demonstrated a positive correlation between MAM-OARGs (PTPN1 and ITPR1) and cellular senescence-related and OA-related genes.
CONCLUSIONS: As a result, our findings can offer new insights into the investigations of MAM-related genes and cellular senescence-related genes, which could be linked to the OA as well as brand-new potential treatment targets.

DOI: https://doi.org/10.1021/acsomega.3c10316
Adv Biol (Weinh). 2024 May 08. e2300288

Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies.

Ruixue Liu, Weilong Hong, Dongyao Hou, He Huang, Chenyang Duan.

  Organelles, substructures in the cytoplasm with specific morphological structures and functions, interact with each other via membrane fusion, membrane transport, and protein interactions, collectively termed organelle interaction. Organelle interaction is a complex biological process involving the interaction and regulation of several organelles, including the interaction between mitochondria-endoplasmic reticulum, endoplasmic reticulum-Golgi, mitochondria-lysosomes, and endoplasmic reticulum-peroxisomes. This interaction enables intracellular substance transport, metabolism, and signal transmission, and is closely related to the occurrence, development, and treatment of many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Herein, the mechanisms and regulation of organelle interactions are reviewed, which are critical for understanding basic principles of cell biology and disease development mechanisms. The findings will help to facilitate the development of novel strategies for disease prevention, diagnosis, and treatment opportunities.

Keywords:  disease therapy; endoplasmic reticulum; lysosome; mitochondria; molecular mechanism; organelle interaction

DOI:  https://doi.org/10.1002/adbi.202300288
FEBS J. 2024 May 05.

Morphodynamical adaptation of the endolysosomal system to stress.

Juliane Da Graça, Cédric Delevoye, Etienne Morel.

  In eukaryotes, the spatiotemporal control of endolysosomal organelles is central to the maintenance of homeostasis. By providing an interface between the cytoplasm and external environment, the endolysosomal system is placed at the forefront of the response to a wide range of stresses faced by cells. Endosomes are equipped with a dedicated set of membrane-associated proteins that ensure endosomal functions as well as crosstalk with the secretory or the autophagy pathways. Morphodynamical processes operate through local spatialization of subdomains, enabling specific remodeling and membrane contact capabilities. Consequently, the plasticity of endolysosomal organelles can be considered a robust and flexible tool exploited by cells to cope with homeostatic deviations. In this review, we provide insights into how the cellular responses to various stresses (osmotic, UV, nutrient deprivation, or pathogen infections) rely on the adaptation of the endolysosomal system morphodynamics.

Keywords:  autophagy; endocytic pathway; endolysosomes; endosomes; lysosome‐related organelles; membrane dynamics and contact sites; organelles; pathogen infection; plasma membrane; stress response

DOI:  https://doi.org/10.1111/febs.17154
Biosystems. 2024 May 06. pii: S0303-2647(24)00112-6. [Epub ahead of print] 105227

Temporal multiscale modeling of biochemical regulatory networks: Calcium-regulated hepatocyte lipid and glucose metabolism.

Arina V Martyshina, Anna G Sirotkina, Irina V Gosteva.

  Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions. Recently, mitochondria-associated membrane (MAM) dysfunction combined with incorrect IP3-receptor regulation has been shown to result in abnormal calcium signaling in hepatocytes. This dysfunction could further lead to hepatic metabolism pathology. However, the exact contribution of MAM dysfunction, incorrect IP3-receptor regulation and insulin resistance to the calcium-insulin-glucagon interplay is not understood yet. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network with a detailed focus on the model construction details besides the biological aspect. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network. We focus on the model construction details, model validation, and predictions. We describe the dynamic regulation of signaling processes by sigmoid Hill function. In particular, we study the effect of both the Hill function slope and the distance between Hill function extremes on metabolic processes in hepatocytes as a model of nonspecific insulin dysfunction. We also address the significant time difference between characteristic time of glucose hepatic processing and a typical calcium oscillation period in hepatocytes. Our modeling results show that calcium signaling dysfunction results in an abnormal increase in postprandial glucose levels, an abnormal glucose decrease in fasting, and a decreased amount of stored glycogen. An insulin dysfunction of glucose phosphorylation, glucose dephosphorylation, and glycogen breakdown also cause a noticeable effect. We also get some insight into the so-called hepatic insulin resistance paradox, confirming the hypothesis regarding indirect insulin action on hepatocytes via dysfunctional adipocyte lipolysis.

Keywords:  Biochemical regulation; Calcium ions; Hepatocyte; Hill function; Insulin resistance; MAMs; Multiscale mathematical modeling

DOI:  https://doi.org/10.1016/j.biosystems.2024.105227