Vol.46 No.5, May 31, 2023 Article TypeJournal ClubMinireviewResearch Article

• Minireview 2023-05-31

  0 792 365

  The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation

  Min-Ji Kim , Hoyul Lee , Dipanjan Chanda , Themis Thoudam , Hyeon-Ji Kang , Robert A. Harris , and In-Kyu Lee

  Mol. Cells 2023; 46(5): 259-267 https://doi.org/10.14348/molcells.2023.2128

  

  

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  Abstract : Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca²⁺ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca²⁺ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca²⁺ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.

• Minireview 2023-05-31

  0 349 89

  The Role of Splicing Factors in Adipogenesis and Thermogenesis

  Yadanar Than Naing and Lei Sun

  Mol. Cells 2023; 46(5): 268-277 https://doi.org/10.14348/molcells.2023.2195

  

  

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  Abstract : Obesity is a significant global health risk that can cause a range of serious metabolic problems, such as type 2 diabetes and cardiovascular diseases. Adipose tissue plays a pivotal role in regulating energy and lipid storage. New research has underlined the crucial role of splicing factors in the physiological and functional regulation of adipose tissue. By generating multiple transcripts from a single gene, alternative splicing allows for a greater diversity of the proteome and transcriptome, which subsequently influence adipocyte development and metabolism. In this review, we provide an outlook on the part of splicing factors in adipogenesis and thermogenesis, and investigate how the different spliced isoforms can affect the development and function of adipose tissue.

• Journal Club 2023-05-31

  0 189 26

  Fission-Fueled Nucleoid Dispersion, a Novel Mitochondrial Metabolic Activation Mechanism

  Jeongah Kim

  Mol. Cells 2023; 46(5): 278-280 https://doi.org/10.14348/molcells.2023.0043

  

  

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• Research Article 2023-05-31

  0 419 138

  Functional Analysis of CXCR3 Splicing Variants and Their Ligands Using NanoBiT-Based Molecular Interaction Assays

  Huong Thi Nguyen , Sunghoon Hurh , Lan Phuong Nguyen , Thai Uy Nguyen , Hee-Kyung Park , Jae Young Seong , Cheol Soon Lee , Byung-Joo Ham , and Jong-Ik Hwang

  Mol. Cells 2023; 46(5): 281-297 https://doi.org/10.14348/molcells.2023.2096

  

  

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  Abstract : CXCR3 regulates leukocyte trafficking, maturation, and various pathophysiological conditions. Alternative splicing generates three CXCR3 isoforms in humans. Previous studies investigated the roles of CXCR3 isoforms, and some biochemical data are not correlated with biological relevance analyses. RT-PCR analyses indicate that most cells express all three splicing variants, suggesting that they may mutually affect the chemokine binding and cellular responses of other splicing variants. Here, we performed an integrative analysis of the functional relations among CXCR3 splicing variants and their chemokine-dependent signaling using NanoBiT live cell protein interaction assays. The results indicated that the CXCR3 N-terminal region affected cell surface expression levels and ligand-dependent activation. CXCR3A was efficiently expressed in the plasma membrane and responded to I-TAC, IP-10, and MIG chemokines. By contrast, CXCR3B had low plasma membrane expression and mediated I-TAC–stimulated cellular responses. CXCR3Alt was rarely expressed on the cell surface and did not mediate any cell responses to the tested chemokines; however, CXCR3Alt negatively affected the plasma membrane expression of CXCR3A and CXCR3B and their chemokine-stimulated cellular responses. Jurkat cells express endogenous CXCR3, and exogenous CXCR3A expression enhanced chemotactic activity in response to I-TAC, IP-10, and MIG. By contrast, exogenous expression of CXCR3B and CXCR3Alt eliminated or reduced the CXCR3A-induced chemotactic activity. The PF-4 chemokine did not activate any CXCR3-mediated cellular responses. NanoBiT technology are useful to integrative studies of CXCR3-mediated cell signaling, and expand our knowledge of the cellular responses mediated by molecular interactions among the splicing variants, including cell surface expression, ligand-dependent receptor activation, and chemotaxis.

• Research Article 2023-05-31

  1 373 169

  Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression

  Haejeong Heo , Hee-Jin Kim , Keeok Haam , Hyun Ahm Sohn , Yang-Ji Shin , Hanyong Go , Hyo-Jung Jung , Jong-Hwan Kim , Sang-Il Lee , Kyu-Sang Song , Min-Ju Kim , Haeseung Lee , Eun-Soo Kwon , Seon-Young Kim , Yong Sung Kim , and Mirang Kim

  Mol. Cells 2023; 46(5): 298-308 https://doi.org/10.14348/molcells.2023.2148

  

  

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  Abstract : Gastric cancer (GC) is a complex disease influenced by multiple genetic and epigenetic factors. Chronic inflammation caused by Helicobacter pylori infection and dietary risk factors can result in the accumulation of aberrant DNA methylation in gastric mucosa, which promotes GC development. Tensin 4 (TNS4), a member of the Tensin family of proteins, is localized to focal adhesion sites, which connect the extracellular matrix and cytoskeletal network. We identified upregulation of TNS4 in GC using quantitative reverse transcription PCR with 174 paired samples of GC tumors and adjacent normal tissues. Transcriptional activation of TNS4 occurred even during the early stage of tumor development. TNS4 depletion in GC cell lines that expressed high to moderate levels of TNS4, i.e., SNU-601, KATO III, and MKN74, reduced cell proliferation and migration, whereas ectopic expression of TNS4 in those lines that expressed lower levels of TNS4, i.e., SNU-638, MKN1, and MKN45 increased colony formation and cell migration. The promoter region of TNS4 was hypomethylated in GC cell lines that showed upregulation of TNS4. We also found a significant negative correlation between TNS4 expression and CpG methylation in 250 GC tumors based on The Cancer Genome Atlas (TCGA) data. This study elucidates the epigenetic mechanism of TNS4 activation and functional roles of TNS4 in GC development and progression and suggests a possible approach for future GC treatments.

• Research Article 2023-05-31

  0 145 39

  Lamin Filament Assembly Derived from the Atomic Structure of the Antiparallel Four-Helix Bundle

  Jinsook Ahn , Inseong Jo , Soyeon Jeong , Jinwook Lee , and Nam-Chul Ha

  Mol. Cells 2023; 46(5): 309-318 https://doi.org/10.14348/molcells.2023.2144

  

  

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  Abstract : The nucleoskeletal protein lamin is primarily responsible for the mechanical stability of the nucleus. The lamin assembly process requires the A11, A22, and ACN binding modes of the coiled-coil dimers. Although X-ray crystallography and chemical cross-linking analysis of lamin A/C have provided snapshots of A11 and ACN binding modes, the assembly mechanism of the entire filament remains to be explained. Here, we report a crystal structure of a coil 2 fragment, revealing the A22 interaction at the atomic resolution. The structure showed detailed structural features, indicating that two coiled-coil dimers of the coil 2 subdomain are separated and then re-organized into the antiparallel-four-helix bundle. Furthermore, our findings suggest that the ACN binding mode between coil 1a and the C-terminal part of coil 2 when the A11 tetramers are arranged by the A22 interactions. We propose a full assembly model of lamin A/C with the curvature around the linkers, reconciling the discrepancy between the in situ and in vitro observations. Our model accounts for the balanced elasticity and stiffness of the nuclear envelopes, which is essential in protecting the cellular nucleus from external pressure.

• Research Article 2023-05-31

  0 376 119

  Ca²⁺-Permeable TRPV1 Receptor Mediates Neuroprotective Effects in a Mouse Model of Alzheimer’s Disease via BDNF/CREB Signaling Pathway

  Juyong Kim , Sangwoo Seo , Jung Han Yoon Park , Ki Won Lee , Jiyoung Kim , and Jin-Chul Kim

  Mol. Cells 2023; 46(5): 319-328 https://doi.org/10.14348/molcells.2023.2156

  

  

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  Abstract : Transient receptor potential vanilloid 1 (TRPV1) protein is a Ca²⁺-permeable non-selective cation channel known for its pain modulation pathway. In a previous study, it was discovered that a triple-transgenic Alzheimer’s disease (AD) mouse model (3xTg-AD^+/+) has anti-AD effects. The expression of proteins in the brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB) pathway in a 3xTg-AD/TRPV1 transgenic mice model was investigated to better understand the AD regulatory effect of TRPV1 deficiency. The results show that TRPV1 deficiency leads to CREB activation by increasing BDNF levels and promoting phosphorylation of tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and CREB in the hippocampus. Additionally, TRPV1 deficiency-induced CREB activation increases the antiapoptotic factor B-cell lymphoma 2 (Bcl-2) gene, which consequently downregulates Bcl-2-associated X (Bax) expression and decreases cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), which leads to the prevention of hippocampal apoptosis. In conclusion, TRPV1 deficiency exhibits neuroprotective effects by preventing apoptosis through the BDNF/CREB signal transduction pathway in the hippocampus of 3xTg-AD mice.