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Colca JR, McCommis KS. Metabolic dysfunction and insulin sensitizers in acute and chronic disease. Expert Opin Investig Drugs 2025; 34:17-26. [PMID: 39912680 DOI: 10.1080/13543784.2025.2463086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/09/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of 'insulin resistance' as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases. AREAS COVERED We review evolving understanding of the mitochondrial pyruvate carrier (MPC) as a mitochondrial mechanism of action of the TZD insulin sensitizers and discuss how reprogramming of mitochondrial metabolism impacts pleotropic pharmacology in multiple tissues. Additional lines of investigation are proposed. EXPERT OPINION A change in paradigm can facilitate rethinking of insulin sensitizers in clinical trials, specifically beyond the treatment of frank type 2 diabetes. There should be broader clinical evaluation of insulin sensitizers in combination with weight loss and lifestyle approaches across diseases/syndromes associated with insulin resistance. Finally, 'connecting all the dots' to unwind the interconnectedness of cell biology involved in the syndromes impacted by metabolic dysfunction and the efficacy of TZD insulin sensitizers may also uncover new molecular targets. New studies should facilitate the discovery and development of novel pharmacologic agents.
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Affiliation(s)
- Jerry R Colca
- Research and Development, Cirius Therapeutics, Kalamazoo, MI, USA
| | - Kyle S McCommis
- Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO, USA
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Hou N, Zhou H, Li J, Xiong X, Deng H, Xiong S. Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm. Immun Inflamm Dis 2024; 12:e1268. [PMID: 39530309 PMCID: PMC11555488 DOI: 10.1002/iid3.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/03/2024] [Accepted: 04/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. AIMS This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. METHODS We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. RESULTS The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. CONCLUSION Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.
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Affiliation(s)
- Ningxin Hou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hongmin Zhou
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jun Li
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoxing Xiong
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hongping Deng
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Sizheng Xiong
- Department of Vascular SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
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Sun X, Wu T, Yang Z, Chen S, Zhao Z, Hu C, Wu S, Wu J, Mao Y, Liu J, Guo C, Cao G, Xu X, Huang S, Liang G. Regulatory role of PDK1 via integrated gene analysis of mitochondria-immune response in periodontitis. Gene 2024; 918:148476. [PMID: 38657876 DOI: 10.1016/j.gene.2024.148476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
AIMS To investigate the association between mitochondrial events and immune response in periodontitis and related regulatory genes. MAIN METHODS Gene expression profiles in gingival tissues were retrieved from the Gene Expression Omnibus. Mitochondria-immune response-related differentially expressed genes (MIR-DEGs) between the healthy and periodontitis samples were determined. WGCNA, GO, and KEGG were used to investigate the function and the enriched pathways of MIR-DEGs. The correlation between MIR-DEGs expression and clinical probing pocket depth was analyzed. The MIR-DEGs were further identified and verified in animal samples. A periodontitis model was established in C57BL/6 mice with silk ligation. Micro-computed tomography was used to assess alveolar bone loss. Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses further validated the differential expression of the MIR-DEGs. KEY FINDINGS A total of ten MIR-DEGs (CYP24A1, PRDX4, GLDC, PDK1, BCL2A1, CBR3, ARMCX3, BNIP3, IFI27, and UNG) were identified, the expression of which could effectively distinguish patients with periodontitis from the healthy controls. Enhanced immune response was detected in the periodontitis group with that in the healthy controls, especially in B cells. PDK1 was a critical MIR-DEG correlated with B cell immune response and clinical periodontal probing pocket depth. Both animal and clinical periodontal samples presented higher gene and protein expression of PDK1 than the control samples. Additionally, PDK1 colocalized with B cells in both animal and clinical periodontal tissues. SIGNIFICANCE Mitochondria participate in the regulation of the immune response in periodontitis. PDK1 may be the key mitochondria-related gene regulating B-cell immune response in periodontitis.
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Affiliation(s)
- Xiaoyu Sun
- Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China; Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China; Department of Periodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Tong Wu
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Zhan Yang
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Shuhong Chen
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Zheyu Zhao
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Chaoming Hu
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Shengzhuang Wu
- School and Hospital of Stomatology, Hangzhou Medical University, Wenzhou, China
| | - Jiayu Wu
- School of Medicine, Jiujiang University, 320 Xunyang East Road, Jiujiang City, Jiangxi Province 332000, China
| | - Yixin Mao
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China; Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Jiefan Liu
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China; Department of Oral and Maxillofacial Surgery/Pathology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Chen Guo
- School/Hospital of Stomatology, Lanzhou University, Lanzhou 730000, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Xiangwei Xu
- Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China.
| | - Shengbin Huang
- Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China.
| | - Guang Liang
- Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China.
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Frye RE, Rincon N, McCarty PJ, Brister D, Scheck AC, Rossignol DA. Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis. Neurobiol Dis 2024; 197:106520. [PMID: 38703861 DOI: 10.1016/j.nbd.2024.106520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
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Affiliation(s)
- Richard E Frye
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Southwest Autism Research and Resource Center, Phoenix, AZ, USA; Rossignol Medical Center, Phoenix, AZ, USA.
| | | | - Patrick J McCarty
- Tulane University School of Medicine, New Orleans, LA 70113, United States of America.
| | | | - Adrienne C Scheck
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, United States of America.
| | - Daniel A Rossignol
- Autism Discovery and Treatment Foundation, Phoenix, AZ, USA; Rossignol Medical Center, Aliso Viejo, CA, USA
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Wang Y, Yang C, Wang Z, Wang Y, Yan Q, Feng Y, Liu Y, Huang J, Zhou J. Epithelial Galectin-3 Induced the Mitochondrial Complex Inhibition and Cell Cycle Arrest of CD8 + T Cells in Severe/Critical COVID-19. Int J Mol Sci 2023; 24:12780. [PMID: 37628961 PMCID: PMC10454470 DOI: 10.3390/ijms241612780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Previous research suggested that the dramatical decrease in CD8+ T cells is a contributing factor in the poor prognosis and disease progression of COVID-19 patients. However, the underlying mechanisms are not fully understood. In this study, we conducted Single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) analysis, which revealed a proliferative-exhausted MCM+FASLGlow CD8+ T cell phenotype in severe/critical COVID-19 patients. These CD8+ T cells were characterized by G2/M cell cycle arrest, downregulation of respiratory chain complex genes, and inhibition of mitochondrial biogenesis. CellChat analysis of infected lung epithelial cells and CD8+ T cells found that the galectin signaling pathway played a crucial role in CD8+ T cell reduction and dysfunction. To further elucidate the mechanisms, we established SARS-CoV-2 ORF3a-transfected A549 cells, and co-cultured them with CD8+ T cells for ex vivo experiments. Our results showed that epithelial galectin-3 inhibited the transcription of the mitochondrial respiratory chain complex III/IV genes of CD8+ T cells by suppressing the nuclear translocation of nuclear respiratory factor 1 (NRF1). Further findings showed that the suppression of NRF1 translocation was associated with ERK-related and Akt-related signaling pathways. Importantly, the galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, thus enhancing the expression of the mitochondrial respiratory chain complex III/IV genes and the mitochondrial biogenesis of CD8+ T cells. Our study provided new insights into the immunopathogenesis of COVID-19 and identified potential therapeutic targets for the prevention and treatment of severe/critical COVID-19 patients.
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Affiliation(s)
- Yudie Wang
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Cheng Yang
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Zhongyi Wang
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yi Wang
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Qing Yan
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Ying Feng
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yanping Liu
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Juan Huang
- Department of Hematology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China
| | - Jingjiao Zhou
- Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China
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Chen J, Ma H, Meng Y, Liu Q, Wang Y, Lin Y, Yang D, Yao W, Wang Y, He X, Li P. Analysis of the mechanism underlying diabetic wound healing acceleration by Calycosin-7-glycoside using network pharmacology and molecular docking. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154773. [PMID: 36990011 DOI: 10.1016/j.phymed.2023.154773] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/27/2023] [Accepted: 03/14/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Diabetic wounds represent a severe clinical challenge in which impaired M2 macrophage polarization and continuous macrophage glycolysis play crucial roles. Calycosin-7-glucoside (CG) is an isoflavone component in Astragali Radix (AR), which has become a research focus for treating diabetic wounds following reports indicating that it has anti-inflammatory effects. However, the mechanism through which CG can treat diabetic wounds is yet to be deciphered. PURPOSE This study aimed to evaluate the therapeutic effect of CG on diabetic wounds and its underlying mechanism. METHODS The potential mechanism underlying the treatment of diabetic wounds by CG was screened using bioinformatics. The therapeutic effects of CG were then investigated using a db/db diabetic wound model. Moreover, an LPS- and IFN-γ-induced RAW264.7 cell inflammation model was used to elucidate the mechanism underlying the therapeutic effects of CG against diabetic wounds. RESULTS Network pharmacology predicted that the AMPK pathway could be the main target through which CG treats diabetic wounds. In db/db diabetic mice, CG could accelerate wound healing and promote granulation tissue regeneration. Protein chip technology revealed that CG increased the production of M-CSF, G-CSF, GM-CSF, IL-10, IL-13, and IL-4 but not that of MCP-1, IL-1β, IL-1α, TNF-α, and TNF-RII. Moreover, CG elevated the proportion of Ly6CLo/- anti-inflammatory monocytes in peripheral blood and M2 macrophages in the wound. The ELISA and flow cytometry analyses revealed that CG enhanced the levels of IL-10, VEGF, CD206, and Arg-1 expression whereas it considerably reduced the levels of IL-1, IL-6, IL-12, TNF-α, CD86, and iNOS expression. Meanwhile, CG increased the macrophage mitochondrial membrane potential and decreased the mitochondrial ADP/ATP ratio and glycolysis rate of M1 macrophages through the ROS/AMPK/STAT6 pathway. CONCLUSIONS The network pharmacology and molecular dockin identified the AMPK pathway as a critical pathway for treating diabetic wounds using topical CG application. CG was found to promote anti-inflammatory monocyte recruitment and decrease the mitochondrial glycolysis rate to induce M2 macrophage polarization via the ROS/AMPK/STAT6 pathway. These results suggest that CG might be a promising therapeutic agent for diabetic wounds.
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Affiliation(s)
- Jia Chen
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Huike Ma
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yujiao Meng
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Qingwu Liu
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yan Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yan Lin
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Danyang Yang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Wentao Yao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Yazhuo Wang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China
| | - Xiujuan He
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
| | - Ping Li
- Beijing University of Chinese Medicine, Beijing 100105, China; Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, No. 23rd Art Museum Back Street, Dongcheng District, Beijing 100010, China.
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Gong M, Choi SC, Park YP, Zou X, Elshikha AS, Gerriets VA, Rathmell JC, Mohamazadeh M, Morel L. Transcriptional and metabolic programs promote the expansion of follicular helper T cells in lupus-prone mice. iScience 2023; 26:106774. [PMID: 37216123 PMCID: PMC10197114 DOI: 10.1016/j.isci.2023.106774] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/28/2023] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
The expansion of follicular helper T (Tfh) cells, which is tightly associated with the development of lupus, is reversed by the inhibition of either glycolysis or glutaminolysis in mice. Here we analyzed the gene expression and metabolome of Tfh cells and naive CD4+ T (Tn) cells in the B6.Sle1.Sle2.Sle3 (triple congenic, TC) mouse model of lupus and its congenic B6 control. Lupus genetic susceptibility in TC mice drives a gene expression signature starting in Tn cells and expanding in Tfh cells with enhanced signaling and effector programs. Metabolically, TC Tn and Tfh cells showed multiple defective mitochondrial functions. TC Tfh cells also showed specific anabolic programs including enhanced glutamate metabolism, malate-aspartate shuttle, and ammonia recycling, as well as altered dynamics of amino acid content and their transporters. Thus, our study has revealed specific metabolic programs that can be targeted to specifically limit the expansion of pathogenic Tfh cells in lupus.
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Affiliation(s)
- Minghao Gong
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Seung-Chul Choi
- Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Yuk Pheel Park
- Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Xueyang Zou
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Ahmed S. Elshikha
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Valerie A. Gerriets
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Jeffrey C. Rathmell
- Vanderbilt Center for Immunobiology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mansour Mohamazadeh
- Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Laurence Morel
- Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX 78229, USA
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Shimura T. Mitochondrial Signaling Pathways Associated with DNA Damage Responses. Int J Mol Sci 2023; 24:ijms24076128. [PMID: 37047099 PMCID: PMC10094106 DOI: 10.3390/ijms24076128] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/14/2023] [Accepted: 03/23/2023] [Indexed: 04/14/2023] Open
Abstract
Under physiological and stress conditions, mitochondria act as a signaling platform to initiate biological events, establishing communication from the mitochondria to the rest of the cell. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species, cytochrome C, and damage-associated molecular patterns act as messengers in metabolism, oxidative stress response, bystander response, apoptosis, cellular senescence, and inflammation response. In this review paper, the mitochondrial signaling in response to DNA damage was summarized. Mitochondrial clearance via fusion, fission, and mitophagy regulates mitochondrial quality control under oxidative stress conditions. On the other hand, damaged mitochondria release their contents into the cytoplasm and then mediate various signaling pathways. The role of mitochondrial dysfunction in radiation carcinogenesis was discussed, and the recent findings on radiation-induced mitochondrial signaling and radioprotective agents that targeted mitochondria were presented. The analysis of the mitochondrial radiation effect, as hypothesized, is critical in assessing radiation risks to human health.
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Affiliation(s)
- Tsutomu Shimura
- Department of Environmental Health, National Institute of Public Health, Wako 351-0197, Saitama, Japan
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Zhang X, Sun J, Zhou M, Li C, Zhu Z, Gan X. The role of mitochondria in the peri-implant microenvironment. Exp Physiol 2023; 108:398-411. [PMID: 36648334 PMCID: PMC10103875 DOI: 10.1113/ep090988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 12/12/2022] [Indexed: 01/18/2023]
Abstract
NEW FINDINGS What is the topic of this review? In this review, we consider the key role of mitochondria in the peri-implant milieu, including the regulation of mitochondrial reactive oxygen species and mitochondrial metabolism in angiogenesis, the polarization of macrophage immune responses, and bone formation and bone resorption during osseointegration. What advances does it highlight? Mitochondria contribute to the behaviours of peri-implant cell lines based on metabolic and reactive oxygen species signalling modulations, which will contribute to the research field and the development of new treatment strategies for improving implant success. ABSTRACT Osseointegration is a dynamic biological process in the local microenvironment adjacent to a bone implant, which is crucial for implant performance and success of the implant surgery. Recently, the role of mitochondria in the peri-implant microenvironment during osseointegration has gained much attention. Mitochondrial regulation has been verified to be essential for cellular events in osseointegration and as a therapeutic target for peri-implant diseases in the peri-implant microenvironment. In this review, we summarize our current knowledge of the key role of mitochondria in the peri-implant milieu, including the regulation of mitochondrial reactive oxygen species and mitochondrial metabolism in angiogenesis, the polarization of macrophage immune responses, and bone formation and resorption during osseointegration, which will contribute to the research field and the development of new treatment strategies to improve implant success. In addition, we indicate limitations in our current understanding of the regulation of mitochondria in osseointegration and suggest topics for further study.
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Affiliation(s)
- Xidan Zhang
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Jiyu Sun
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Min Zhou
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Chen Li
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Zhuoli Zhu
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xueqi Gan
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
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Guo Z, Wang Z, Gao Z, Feng T, Gao Y, Yin Z, Tian Z, Liu Y, Mao X, Xiang C. The status and trends of mitochondrial dynamics research: A global bibliometric and visualized analysis. J Bioenerg Biomembr 2023; 55:43-57. [PMID: 36807837 PMCID: PMC9942064 DOI: 10.1007/s10863-023-09959-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/06/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND Mitochondria are remarkably dynamic organelles encapsulated by bilayer membranes. The dynamic properties of mitochondria are critical for energy production. AIMS The aim of our study is to investigate the global status and trends of mitochondrial dynamics research and predict popular topics and directions in the field. METHODS Publications related to the studies of mitochondrial dynamics from 2002 to 2021 were retrieved from Web of Science database. A total of 4,576 publications were included. Bibliometric analysis was conducted by visualization of similarities viewer and GraphPadPrism 5 software. RESULTS There is an increasing trend of mitochondrial dynamics research during the last 20 years. The cumulative number of publications about mitochondrial dynamics research followed the logistic growth model [Formula: see text]. The USA made the highest contributions to the global research. The journal Biochimica et Biophysica Acta (BBA)-Molecular Cell Research had the largest publication numbers. Case Western Reserve University is the most contributive institution. The main research orientation and funding agency were cell biology and HHS. All keywords related studies could be divided into three clusters: "Related disease research", "Mechanism research" and "Cell metabolism research". CONCLUSIONS Attention should be drawn to the latest popular research and more efforts will be put into mechanistic research, which may inspire new clinical treatments for the associated diseases.
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Affiliation(s)
- Zijian Guo
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zehua Wang
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhenzhong Gao
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Tengda Feng
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yingjie Gao
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhiwen Yin
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zui Tian
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yang Liu
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xingjia Mao
- Department of Basic Medicine Sciences, and Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Chuan Xiang
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China.
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11
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Markouli M, Strepkos D, Papavassiliou KA, Papavassiliou AG, Piperi C. Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis. Cancers (Basel) 2022; 14:2655. [PMID: 35681635 PMCID: PMC9179868 DOI: 10.3390/cancers14112655] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/14/2022] [Accepted: 05/24/2022] [Indexed: 02/06/2023] Open
Abstract
Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.
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12
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Dexmedetomidine Can Enhance PINK1/Parkin-Mediated Mitophagy in MPTP-Induced PD Mice Model by Activating AMPK. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7511393. [PMID: 35528513 PMCID: PMC9068320 DOI: 10.1155/2022/7511393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/05/2022] [Accepted: 03/23/2022] [Indexed: 11/24/2022]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Our previous study has shown that dexmedetomidine (Dex) can protect mitochondrial function and reduce apoptosis in MPP+-induced SH-SY5Y cells. Evidences have shown that mitophagy is related to the development of PD. In this study, we investigated whether Dex can enhance mitophagy in MPTP-induced mice to play a neuroprotective effect. In our experiment, mice were injected with MPTP 30 mg/kg intraperitoneally for 5 consecutive days to establish a PD subacute model. Dex (30, 50, and 100 μg/kg) was injected intraperitoneally 30 minutes before each injection of MPTP, respectively. Our results showed that Dex (50 μg/kg) most significantly attenuated MPTP-induced motor dysfunction and restored TH-positive neurons in the SN, increased the expression of the antiapoptotic protein Bcl-2, and decreased the expression of apoptotic proteins cleaved casepase3, cleaved casepase9, and Bax. Moreover, Dex increased the activity of mitochondrial Complexes I-IV and decreased the level of oxidative stress, manifesting as decreased MDA levels and increased SOD and GSH-PX levels. Besides, under transmission electron microscopy, Dex increased the mitophagosome which is an autophagosome with a mitochondrion-like structure inside under the electron microscope. In addition, Dex could also increase the expression of mitophagy-related proteins p-AMPK, LC3II/I, PINK1, and Parkin and decrease P62. However, after using Compound C (CC, 10 mg/kg, AMPK inhibitor), the effects of Dex on increasing PINK1/Parkin-induced mitophagy and neuroprotection were attenuated. In conclusion, Dex may improve mitochondrial function by activating AMPK to enhance PINK1/Parkin-induced mitophagy, thereby protecting dopaminergic neurons.
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13
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Hydroxytyrosol Attenuates High-Fat-Diet-Induced Oxidative Stress, Apoptosis and Inflammation of Blunt Snout Bream (Megalobrama amblycephala) through Its Regulation of Mitochondrial Homeostasis. FISHES 2022. [DOI: 10.3390/fishes7020078] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The present study was conducted to investigate the effects of dietary hydroxytyrosol (HT) on oxidative stress, inflammation and mitochondrial homeostasis in blunt snout bream (Megalobrama amblycephala). Fish were fed a low-fat diet (LFD, 5% lipid), a high-fat diet (HFD, 15% lipid), an LFD supplementing 200 mg/kg HT, or an HFD supplementing 200 mg/kg HT. After 10-week feeding, significant reduction of growth was observed in fish fed HFD, compared with other groups. HFD caused oxidative stress and more apoptosis of hepatocytes, while HT addition resulted in significant decrease of ROS and MDA contents, and the apoptotic hepatocytes. Moreover, the expression of genes involving inflammation of HFD group were elevated. Supplementing HT to HFD can attenuate this. All the activities of complexes of mitochondria in the HFD group were decreased compared with those in the LFD group, while supplementing HT to HFD significantly increased complex I-III activities. Furthermore, HFD downregulated the expressions of Atg5 and NRF-1 which induced the failure of mitophagy and biogenesis, while, supplementing HT to HFD reversed these expressions involving mitochondrial autophagy and biogenesis. In summary, adding HT to HFD relieved oxidative stress, apoptosis and inflammation, likely due to its regulation of mitochondrial homeostasis.
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14
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Liang H, Dong S, Fu W, Zhang S, Yu W, Dong F, He B, Wang J, Gao Y, Zhou Y, Ru Y. Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation. Stem Cell Rev Rep 2022; 18:2179-2194. [DOI: 10.1007/s12015-022-10354-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/07/2022] [Indexed: 12/23/2022]
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15
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Wen S, Jiang Y, Liang S, Cheng Z, Zhu X, Guo Q. Opioids Regulate the Immune System: Focusing on Macrophages and Their Organelles. Front Pharmacol 2022; 12:814241. [PMID: 35095529 PMCID: PMC8790028 DOI: 10.3389/fphar.2021.814241] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/20/2021] [Indexed: 01/02/2023] Open
Abstract
Opioids are the most widely used analgesics and therefore have often been the focus of pharmacological research. Macrophages are the most plastic cells in the hematopoietic system. They show great functional diversity in various organism tissues and are an important consideration for the study of phagocytosis, cellular immunity, and molecular immunology. The expression of opioid receptors in macrophages indicates that opioid drugs act on macrophages and regulate their functions. This article reviewed the collection of research on effects of opioids on macrophage function. Studies show that opioids, both endogenous and exogenous, can affect the function of macrophages, effecting their proliferation, chemotaxis, transport, phagocytosis, expression of cytokines and chemokine receptors, synthesis and secretion of cytokines, polarization, and apoptosis. Many of these effects are closely associated with mitochondrial function and functions of other organelles in macrophages. Therefore, in depth research into effects of opioids on macrophage organelles may lead to some interesting new discoveries. In view of the important role of macrophages in HIV infection and tumor progression, this review also discusses effects of opioids on macrophages in these two pathological conditions.
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Affiliation(s)
- Shaohua Wen
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Jiang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shuang Liang
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhigang Cheng
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyan Zhu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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16
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Hastreiter AA, Paredes LC, Saraiva Camara NO. Metabolic requirement for macrophages. MACROPHAGES IN THE HUMAN BODY 2022:49-66. [DOI: 10.1016/b978-0-12-821385-8.00010-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Li M, Ge Q, Du H, Lin S. Tricholoma matsutake-Derived Peptides Ameliorate Inflammation and Mitochondrial Dysfunction in RAW264.7 Macrophages by Modulating the NF-κB/COX-2 Pathway. Foods 2021; 10:2680. [PMID: 34828964 PMCID: PMC8621704 DOI: 10.3390/foods10112680] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
Tricholoma matsutake is an edible fungus that contains various bioactive substances, some of them with immunostimulatory properties. Presently, there is limited knowledge about the functional components of T. matsutake. Our aim was to evaluate the protective effects and molecular mechanisms of two T. matsutake-derived peptides, SDLKHFPF and SDIKHFPF, on lipopolysaccharide (LPS)-induced mitochondrial dysfunction and inflammation in RAW264.7 macrophages. Tricholoma matsutake peptides significantly ameliorated the production of inflammatory cytokines and inhibited the expression of COX-2, iNOS, IKKβ, p-IκB-α, and p-NF-κB. Immunofluorescence assays confirmed the inhibitory effect of T. matsutake peptides on NF-κB/p65 nuclear translocation. Furthermore, the treatment with T. matsutake peptides prevented the accumulation of reactive oxygen species, increased the Bcl-2/Bax ratio, reversed the loss of mitochondrial membrane potential, and rescued abnormalities in cellular energy metabolism. These findings indicate that T. matsutake peptides can effectively inhibit the activation of NF-κB/COX-2 and may confer an overall protective effect against LPS-induced cell damage.
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Affiliation(s)
| | | | | | - Songyi Lin
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China; (M.L.); (Q.G.); (H.D.)
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18
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Zhu YX, Huang JQ, Ming YY, Zhuang Z, Xia H. Screening of key biomarkers of tendinopathy based on bioinformatics and machine learning algorithms. PLoS One 2021; 16:e0259475. [PMID: 34714891 PMCID: PMC8555777 DOI: 10.1371/journal.pone.0259475] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/19/2021] [Indexed: 12/30/2022] Open
Abstract
Tendinopathy is a complex multifaceted tendinopathy often associated with overuse and with its high prevalence resulting in significant health care costs. At present, the pathogenesis and effective treatment of tendinopathy are still not sufficiently elucidated. The purpose of this research is to intensely explore the genes, functional pathways, and immune infiltration characteristics of the occurrence and development of tendinopathy. The gene expression profile of GSE106292, GSE26051 and GSE167226 are downloaded from GEO (NCBI comprehensive gene expression database) and analyzed by WGCNA software bag using R software, GSE26051, GSE167226 data set is combined to screen the differential gene analysis. We subsequently performed gene enrichment analysis of Gene Ontology (GO) and "Kyoto Encyclopedia of Genes and Genomes" (KEGG), and immune cell infiltration analysis. By constructing the LASSO regression model, Support vector machine (SVM-REF) and Gaussian mixture model (GMMs) algorithms are used to screen, to identify early diagnostic genes. We have obtained a total of 171 DEGs through WGCNA analysis and differentially expressed genes (DEGs) screening. By GO and KEGG enrichment analysis, it is found that these dysregulated genes were related to mTOR, HIF-1, MAPK, NF-κB and VEGF signaling pathways. Immune infiltration analysis showed that M1 macrophages, activated mast cells and activated NK cells had infiltration significance. After analysis of THE LASSO SVM-REF and GMMs algorithms, we found that the gene MACROD1 may be a gene for early diagnosis. We identified the potential of tendon disease early diagnosis way and immune gene regulation MACROD1 key infiltration characteristics based on comprehensive bioinformatics analysis. These hub genes and functional pathways may as early biomarkers of tendon injuries and molecular therapy level target is used to guide drug and basic research.
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Affiliation(s)
- Ya xi Zhu
- District 1, Department of Orthopedics, Xiangtan Central Hospital, Yuhu District, Xiangtan City, Hunan Province, China
- Nanhua University, Hengyang City, Hunan Province, China
| | - Jia qiang Huang
- District 1, Department of Orthopedics, Xiangtan Central Hospital, Yuhu District, Xiangtan City, Hunan Province, China
| | - Yu yang Ming
- Nanhua University, Hengyang City, Hunan Province, China
- Department of Orthopedics, Xiangtan Central Hospital, Yuhu District, Xiangtan City, Hunan Province, China
| | - Zhao Zhuang
- Academy of Anesthesiology, Weifang Medical University, Weifang, China
| | - Hong Xia
- Department of Orthopedics, Xiangtan Central Hospital, Yuhu District, Xiangtan City, Hunan Province, China
- * E-mail:
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19
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Orekhov AN, Poznyak AV, Sobenin IA, Nikifirov NN, Ivanova EA. Mitochondrion as a Selective Target for the Treatment of Atherosclerosis: Role of Mitochondrial DNA Mutations and Defective Mitophagy in the Pathogenesis of Atherosclerosis and Chronic Inflammation. Curr Neuropharmacol 2021; 18:1064-1075. [PMID: 31744449 PMCID: PMC7709151 DOI: 10.2174/1570159x17666191118125018] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/21/2019] [Accepted: 11/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques. OBJECTIVES Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently, there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease. RESULTS Mitochondria of blood and arterial wall cells appear to be one of the important factors in disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment. CONCLUSION Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation.
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Affiliation(s)
- Alexander N Orekhov
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow 121609, Russian Federation,Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russian, Federation,Institute of Human Morphology, Moscow 117418, Russian Federation
| | - Anastasia V Poznyak
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow 121609, Russian Federation
| | - Igor A Sobenin
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow 121609, Russian Federation,Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russian, Federation,Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Str., 121552 Moscow, Russia
| | - Nikita N Nikifirov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russian, Federation,Laboratory of Medical Genetics, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Str., 121552 Moscow, Russia,Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, Moscow 119334, Russia
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20
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Emam M, Tabatabaei S, Sargolzaei M, Mallard B. Response to Oxidative Burst-Induced Hypoxia Is Associated With Macrophage Inflammatory Profiles as Revealed by Cellular Genome-Wide Association. Front Immunol 2021; 12:688503. [PMID: 34220845 PMCID: PMC8253053 DOI: 10.3389/fimmu.2021.688503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/03/2021] [Indexed: 12/27/2022] Open
Abstract
Background In mammalian species, hypoxia is a prominent feature of inflammation. The role of hypoxia in regulating macrophage responses via alteration in metabolic pathways is well established. Recently, oxidative burst-induced hypoxia has been shown in murine macrophages after phagocytosis. Despite the available detailed information on the regulation of macrophage function at transcriptomic and epigenomic levels, the association of genetic polymorphism and macrophage function has been less explored. Previously, we have shown that host genetics controls approximately 80% of the variation in an oxidative burst as measured by nitric oxide (NO-). Further studies revealed two clusters of transcription factors (hypoxia-related and inflammatory-related) are under the genetic control that shapes macrophages’ pro-inflammatory characteristics. Material and Methods In the current study, the association between 43,066 autosomal Single Nucleic Polymorphism (SNPs) and the ability of MDMs in production of NO- in response to E. coli was evaluated in 58 Holstein cows. The positional candidate genes near significant SNPs were selected to perform functional analysis. In addition, the interaction between the positional candidate genes and differentially expressed genes from our previous study was investigated. Results Sixty SNPs on 22 chromosomes of the bovine genome were found to be significantly associated with NO- production of macrophages. The functional genomic analysis showed a significant interaction between positional candidate genes and mitochondria-related differentially expressed genes from the previous study. Further examination showed 7 SNPs located in the vicinity of genes with roles in response to hypoxia, shaping approximately 73% of the observed individual variation in NO- production by MDM. Regarding the normoxic condition of macrophage culture in this study, it was hypothesized that oxidative burst is responsible for causing hypoxia at the cellular level. Conclusion The results suggest that the genetic polymorphism via regulation of response to hypoxia is a candidate step that perhaps shapes macrophage functional characteristics in the pathway of phagocytosis leading to oxidative burst, hypoxia, cellular response to hypoxia and finally the pro-inflammatory responses. Since all cells in one individual carry the same alleles, the effect of genetic predisposition of sensitivity to hypoxia will likely be notable on the clinical outcome to a broad range of host-pathogen interactions.
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Affiliation(s)
- Mehdi Emam
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.,Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Saeid Tabatabaei
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Mehdi Sargolzaei
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.,Select Sires Inc., Plain City, OH, United States
| | - Bonnie Mallard
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.,Center for Genetic Improvement of Livestock, Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
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21
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Huang Y, Wang T, Tan Q, He D, Wu M, Fan J, Yang J, Zhong C, Li K, Zhang J. Smart Stimuli-Responsive and Mitochondria Targeting Delivery in Cancer Therapy. Int J Nanomedicine 2021; 16:4117-4146. [PMID: 34163163 PMCID: PMC8214531 DOI: 10.2147/ijn.s315368] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/22/2021] [Indexed: 01/02/2023] Open
Abstract
Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.
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Affiliation(s)
- Yongjia Huang
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
| | - Tingting Wang
- Biochemistry and Molecular Biology Laboratory, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People's Republic of China
| | - Qunyou Tan
- Department of Thoracic Surgery, Daping Hospital of Army Medical University, PLA, Chongqing, People's Republic of China
| | - Dan He
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
| | - Mingjun Wu
- Institute of Life Science, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jingchuan Fan
- Institute of Life Science, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jie Yang
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
| | - Cailing Zhong
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
| | - Kailing Li
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
| | - Jingqing Zhang
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People's Republic of China
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22
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Planat-Benard V, Varin A, Casteilla L. MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism. Front Immunol 2021; 12:626755. [PMID: 33995350 PMCID: PMC8120150 DOI: 10.3389/fimmu.2021.626755] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials (immunomodulatory, anti-bacterial, anti-inflammatory, anti-oxidant defenses and metabolic adaptation…) and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation.
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Affiliation(s)
- Valerie Planat-Benard
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Audrey Varin
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Louis Casteilla
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
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23
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Woodley SB, Mould RR, Sahuri-Arisoylu M, Kalampouka I, Booker A, Bell JD. Mitochondrial Function as a Potential Tool for Assessing Function, Quality and Adulteration in Medicinal Herbal Teas. Front Pharmacol 2021; 12:660938. [PMID: 33981240 PMCID: PMC8107435 DOI: 10.3389/fphar.2021.660938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/29/2021] [Indexed: 11/13/2022] Open
Abstract
Quality control has been a significant issue in herbal medicine since herbs became widely used to heal. Modern technologies have improved the methods of evaluating the quality of medicinal herbs but the methods of adulterating them have also grown in sophistication. In this paper we undertook a comprehensive literature search to identify the key analytical techniques used in the quality control of herbal medicine, reviewing their uses and limitations. We also present a new tool, based on mitochondrial profiling, that can be used to measure medicinal herbal quality. Besides being fundamental to the energy metabolism required for most cellular activities, mitochondria play a direct role in cellular signalling, apoptosis, stress responses, inflammation, cancer, ageing, and neurological function, mirroring some of the most common reasons people take herbal medicines. A fingerprint of the specific mitochondrial effects of medicinal herbs can be documented in order to assess their potential efficacy, detect adulterations that modulate these effects and determine the relative potency of batches. Furthermore, through this method it will be possible to assess whole herbs or complex formulas thus avoiding the issues inherent in identifying active ingredients which may be complex or unknown. Thus, while current analytical methods focus on determining the chemical quality of herbal medicines, including adulteration and contamination, mitochondrial functional analysis offers a new way of determining the quality of plant derived products that is more closely linked to the biological activity of a product and its potential clinical effectiveness.
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Affiliation(s)
- Steven B Woodley
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom
| | - Rhys R Mould
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom
| | - Meliz Sahuri-Arisoylu
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom.,Health Innovation Ecosystem, University of Westminster, London, United Kingdom
| | - Ifigeneia Kalampouka
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom
| | - Anthony Booker
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom.,Research Group 'Pharmacognosy and Phytotherapy', UCL School of Pharmacy, London, United Kingdom
| | - Jimmy D Bell
- Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, United Kingdom
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24
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Virtuoso A, Giovannoni R, De Luca C, Gargano F, Cerasuolo M, Maggio N, Lavitrano M, Papa M. The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence. Int J Mol Sci 2021; 22:3301. [PMID: 33804873 PMCID: PMC8036663 DOI: 10.3390/ijms22073301] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
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Affiliation(s)
- Assunta Virtuoso
- Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘‘Luigi Vanvitelli”, 80138 Naples, Italy; (A.V.); (F.G.); (M.C.); (M.P.)
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
| | | | - Ciro De Luca
- Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘‘Luigi Vanvitelli”, 80138 Naples, Italy; (A.V.); (F.G.); (M.C.); (M.P.)
| | - Francesca Gargano
- Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘‘Luigi Vanvitelli”, 80138 Naples, Italy; (A.V.); (F.G.); (M.C.); (M.P.)
| | - Michele Cerasuolo
- Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘‘Luigi Vanvitelli”, 80138 Naples, Italy; (A.V.); (F.G.); (M.C.); (M.P.)
| | - Nicola Maggio
- Department of Neurology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel;
- Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 5211401, Israel
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
| | - Michele Papa
- Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ‘‘Luigi Vanvitelli”, 80138 Naples, Italy; (A.V.); (F.G.); (M.C.); (M.P.)
- SYSBIO Centre of Systems Biology ISBE-IT, University of Milano-Bicocca, 20126 Milan, Italy
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25
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Huang Z, Li N, Zhang X, Xiao Y. Mitochondria-Anchored Molecular Thermometer Quantitatively Monitoring Cellular Inflammations. Anal Chem 2021; 93:5081-5088. [PMID: 33729754 DOI: 10.1021/acs.analchem.0c04547] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Temperature in mitochondria can be a critical indicator of cell metabolism. Given the highly dynamic and inhomogeneous nature of mitochondria, it remains a big challenge to quantitatively monitor the local temperature changes during different cellular processes. To implement this task, we extend our strategy on mitochondria-anchored thermometers from "on-off" probe Mito-TEM to a ratiometric probe Mito-TEM 2.0 based on the Förster resonance energy transfer mechanism. Mito-TEM 2.0 exhibits not only a sensitive response to temperature through the ratiometric changes of dual emissions but also the specific immobilization in mitochondria via covalent bonds. Both characters support accurate and reliable detection of local temperature for a long time, even in malfunctioning mitochondria. By applying Mito-TEM 2.0 in fluorescence ratiometric imaging of cells and zebrafishes, we make a breakthrough in the quantitative visualization of mitochondrial temperature rises in different inflammation states.
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Affiliation(s)
- Zhenlong Huang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Ning Li
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Xinfu Zhang
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
| | - Yi Xiao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
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26
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Patrick KL, Watson RO. Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection. Infect Immun 2021; 89:e00687-20. [PMID: 33558322 PMCID: PMC8090963 DOI: 10.1128/iai.00687-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for cross talk or synergy between bacterium- and mitochondrion-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking, and intriguing, in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages, leading to metabolic changes and triggering potent innate immune responses. Research from our laboratories and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyperactivating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrion-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.
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Affiliation(s)
- Kristin L Patrick
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health, College of Medicine, Bryan, Texas, USA
| | - Robert O Watson
- Department of Microbial Pathogenesis and Immunology, Texas A&M Health, College of Medicine, Bryan, Texas, USA
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27
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From Mitochondria to Atherosclerosis: The Inflammation Path. Biomedicines 2021; 9:biomedicines9030258. [PMID: 33807807 PMCID: PMC8000234 DOI: 10.3390/biomedicines9030258] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 02/26/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments.
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28
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Caicedo A, Zambrano K, Sanon S, Luis Vélez J, Montalvo M, Jara F, Moscoso SA, Vélez P, Maldonado A, Velarde G. The diversity and coexistence of extracellular mitochondria in circulation: A friend or foe of the immune system. Mitochondrion 2021; 58:270-284. [PMID: 33662580 DOI: 10.1016/j.mito.2021.02.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 02/10/2021] [Accepted: 02/18/2021] [Indexed: 01/22/2023]
Abstract
The diversity and coexistence of extracellular mitochondria may have a key role in the maintenance of health and progression of disease. Studies report that active mitochondria can be found physiologically outside of cells and circulating in the blood without inducing an inflammatory response. In addition, inactive or harmed mitochondria have been recognized as activators of immune cells, as they play an essential role in diseases characterized by the metabolic deregulation of these cells, such as sepsis. In this review we analyze key aspects regarding the existence of a diversity of extracellular mitochondria, their coexistence in body fluids and their effects on various immune cells. Additionally, we introduce models of how extracellular mitochondria could be interacting to maintain health and affect disease prognosis. Unwrapped mitochondria (freeMitos) can exist as viable, active, inactive or harmed organelles. Mitochondria can also be found wrapped in a membrane (wrappedMitos) that may differ depending on the cell of origin. Mitochondrial fragments can also be present in various body fluids as DAMPs, as mtDNA enclosed in vesicles or as circulating-cell-free mtDNA (ccf-mtDNA). Interestingly, the great quantity of evidence regarding the levels of ccf-mtDNA and their correlation with aging and disease allows for the identification of the diversity, but not type, of extracellular mitochondria. The existence of a diversity of mitochondria and their effects on immune cells opens a new concept in the biomedical field towards the understanding of health, the progression of disease and the development of mitochondria as therapeutic agents.
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Affiliation(s)
- Andrés Caicedo
- Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador; Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; Sistemas Médicos SIME, Universidad San Francisco de Quito, Quito, Ecuador.
| | - Kevin Zambrano
- Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador; Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands; Instituto de Neurociencias, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Serena Sanon
- Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; Cornell University - Ithaca, United States
| | - Jorge Luis Vélez
- Universidad Central del Ecuador, Facultad de Ciencias Médicas, Quito, Ecuador; Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
| | - Mario Montalvo
- Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
| | - Fernando Jara
- Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
| | - Santiago Aguayo Moscoso
- Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
| | - Pablo Vélez
- Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
| | - Augusto Maldonado
- Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, United States; Hospital General Docente de Calderón, Quito, Ecuador
| | - Gustavo Velarde
- Universidad Central del Ecuador, Facultad de Ciencias Médicas, Quito, Ecuador; Hospital Pablo Arturo Suárez, Unidad de Terapia Intensiva y Centro de Investigación Clínica, Quito, Ecuador
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29
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Qing J, Zhang Z, Novák P, Zhao G, Yin K. Mitochondrial metabolism in regulating macrophage polarization: an emerging regulator of metabolic inflammatory diseases. Acta Biochim Biophys Sin (Shanghai) 2020; 52:917-926. [PMID: 32785581 DOI: 10.1093/abbs/gmaa081] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Indexed: 12/24/2022] Open
Abstract
As a major type of immune cells with heterogeneity and plasticity, macrophages are classically divided into inflammatory (M1) and alternative/anti-inflammatory (M2) types and play a crucial role in the progress of the inflammatory diseases. Recent studies have shown that metabolism is an important determinant of macrophage phenotype. Mitochondria, one of the most important compartments involving cell metabolism, are closely associated with the regulation of cell functions. In most types of cell, mitochondrial oxidative phosphorylation (OXPHOS) is the primary mode of cellular energy production. However, mitochondrial OXPHOS is inhibited in activated M1 macrophages, rendering them unable to be converted into M2 phenotype. Thus, mitochondrial metabolism is a crucial regulator in macrophage functions. This review summarizes the roles of mitochondria in macrophage polarization and analyzes the molecular mechanisms underlying mitochondrial metabolism and function, which may provide new approaches for the treatment of metabolic inflammatory diseases.
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Affiliation(s)
- Jina Qing
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
- Research Lab of translational medicine, Hengyang Medical College, University of South China, Hengyang 421001, China
| | - Zizhen Zhang
- School of Medicine, Hunan Polytechnic of Environment and Biology, Hengyang 421001, China
| | - Petr Novák
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
| | - Guojun Zhao
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan City People's Hospital, Qingyuan 511518, China
| | - Kai Yin
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541100, China
- Research Lab of translational medicine, Hengyang Medical College, University of South China, Hengyang 421001, China
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30
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Mitochondrial function in immune cells in health and disease. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165845. [PMID: 32473386 DOI: 10.1016/j.bbadis.2020.165845] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/18/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
One of the main functions of mitochondria is production of ATP for cellular energy needs, however, it becomes more recognized that mitochondria are involved in differentiation and activation processes of immune cells. Upon activation, immune cells have a high need for energy. Immune cells have different strategies to generate this energy. In pro-inflammatory cells, such as activated monocytes and activated T and B cells, the energy is generated by increasing glycolysis, while in regulatory cells, such as regulatory T cells or M2 macrophages, energy is generated by increasing mitochondrial function and beta-oxidation. Except for being important for energy supply during activation, mitochondria also induce immune responses. During an infection, they release mitochondrial danger associated molecules (DAMPs) that resemble structures of bacterial derived pathogen associated molecular patterns (PAMPs). Such mitochondrial DAMPS are for instance mitochondrial DNA with hypomethylated CpG motifs or a specific lipid that is only present in prokaryotic bacteria and mitochondria, i.e. cardiolipin. Via release of such DAMPs, mitochondria guide the immune response towards an inflammatory response against pathogens. This is an important mechanism in early detection of an infection and in stimulating and sustaining immune responses to fight infections. However, mitochondrial DAMPs may also have a negative impact. If mitochondrial DAMPs are released by damaged cells, without the presence of an infection, such as after a trauma, mitochondrial DAMPs may induce an undesired inflammatory response, resulting in tissue damage and organ dysfunction. Thus, immune cells have developed mechanisms to prevent such undesired immune activation by mitochondrial components. In the present narrative review, we will describe the current view of mitochondria in regulation of immune responses. We will also discuss the current knowledge on disturbed mitochondrial function in immune cells in various immunological diseases.
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31
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Anderson G, Maes M. Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Suboptimal Mitochondrial Function: Assessment, Treatment and Classification Implications. Curr Top Med Chem 2020; 20:524-539. [DOI: 10.2174/1568026620666200131094445] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 02/08/2023]
Abstract
:
The gut and mitochondria have emerged as two important hubs at the cutting edge of research
across a diverse array of medical conditions, including most psychiatric conditions. This article highlights
the interaction of the gut and mitochondria over the course of development, with an emphasis on
the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical
conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut
permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis
modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also
modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations
in the activity of reactive cells over the course of development are proposed to be an important determinant
of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress,
also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative
stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised
ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on
daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin.
Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently,
gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of
mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition
of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl-
CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria
and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function.
This has a number of treatment implications across psychiatric and wider medical conditions, including
the utilization of sodium butyrate and melatonin.
:
Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic
homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune
cells.
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Affiliation(s)
- George Anderson
- CRC Scotland & London, Eccleston Square, London, United Kingdom
| | - Michael Maes
- Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
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32
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Inhibition of nuclear factor kappa B as a mechanism of Danshensu during Toll-like receptor 2-triggered inflammation in macrophages. Int Immunopharmacol 2020; 83:106419. [PMID: 32200153 DOI: 10.1016/j.intimp.2020.106419] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 03/13/2020] [Accepted: 03/13/2020] [Indexed: 01/08/2023]
Abstract
Danshensu (DSS) is a water-soluble phenolic compound in Danshen (Salvia Miltiorrhiza Radix et Rhizoma). Although various pharmacological activities have been recognized, little is known regarding its anti-inflammatory effect and related molecular mode of action. In the current study, bone marrow-derived macrophages (BMMs) were activated by a Toll-like receptor 2 (TLR2) agonist Pam3CSK4 with or without DSS intervention. Production of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-12 (IL-12) was detected by both enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR). Activation of signaling pathways involving nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) was assessed by Western blot. Additionally, RNA sequencing (RNA-seq) combined with bioinformatics analyses was applied to investigate the molecular mechanisms of DSS. Emphasis was placed on the construction of the protein-protein interaction (PPI) network and transcription factor (TF) enrichment analysis of data including co-regulated differentially expressed genes (DEGs) in the Pam3CSK4 vs. control and DSS vs. Pam3CSK4 groups. The RT-qPCR and ELISA results showed that DSS effectively inhibited the expressions of IL-6 and IL-12, indicating a significant anti-inflammatory effect. Western blot verified that DSS suppressed the phosphorylation of p65, which was in accordance with the results of the TF enrichment analysis. Additionally, the PPI network analysis showed several key molecules, including lactoferrin (Ltf), CC-chemokine receptor 7 (Ccr7), interferon-gamma (IFN-γ) and C-X-C motif chemokine ligand 9 (Cxcl9), to be regulatory genes that responded to DSS treatment. Overall, our study revealed that DSS has a pronounced anti-inflammatory effect involving TLR2 and macrophages through the NF-κB signaling pathway, which supports the novel application of DSS in the treatment of relevant diseases including atherosclerosis and ischemic or ischemic/perfusion injury of the heart and brain.
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33
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CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 2020; 21:298-308. [PMID: 32066953 PMCID: PMC7043937 DOI: 10.1038/s41590-019-0589-5] [Citation(s) in RCA: 445] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/19/2019] [Indexed: 01/08/2023]
Abstract
Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
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Abstract
Apart from reliable management of the "powerhouse" of the cell, mitochondria faithfully orchestrate a diverse array of important and critical functions in governing cellular signaling, apoptosis, autophagy, mitophagy and innate and adaptive immune system. Introduction of instability and imbalance in the mitochondrial own genome or the nuclear encoded mitochondrial proteome would result in the manifestation of various diseases through alterations in the oxidative phosphorylation system (OXPHOS) and nuclear-mitochondria retrograde signaling. Understanding mitochondrial biology and dynamism are thus of paramount importance to develop strategies to prevent or treat various diseases caused due to mitochondrial alterations.
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Affiliation(s)
- Santanu Dasgupta
- Department of Medicine, The University of Texas Health Science Center at Tyler, Tyler, Texas, USA
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35
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Zhu Z, Zheng L, Li Y, Huang T, Chao YC, Pan L, Zhu H, Zhao Y, Yu W, Li P. Potential Immunotherapeutic Targets on Myeloid Cells for Neurovascular Repair After Ischemic Stroke. Front Neurosci 2019; 13:758. [PMID: 31447626 PMCID: PMC6696904 DOI: 10.3389/fnins.2019.00758] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/08/2019] [Indexed: 12/11/2022] Open
Abstract
Neurological deficits and cognitive dysfunctions caused by acute ischemic stroke pose enormous burden to the stroke families and the communities. Restoration of the normal function of the neurovascular unit following ischemic stroke is critical for improving neurological recovery and cognitive functions after stroke. Recent evidence suggests that the myeloid cells including both the resident microglia and infiltrating monocytes/macrophages and neutrophils are highly plastic in response to the environmental cues. They intimately interact with multiple components of the neurovascular unit in response to the alarmins, danger associated pattern molecules (DAMPs) and other signals released from the ischemic brain. The aim of this review is to discuss the reciprocal interactions between the myeloid cells and the ischemic neurovascular unit during the late repair phase of cerebral ischemic stroke. We also summarize potential immunotherapeutic targets on myeloid cells and new therapeutic approaches targeting myeloid cells, such as cell transplantation, mitochondrial dynamic and extracellular vesicles-based therapy et al to enhance neurovascular repair for better stroke recovery.
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Affiliation(s)
- Ziyu Zhu
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Li Zheng
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yan Li
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Tingting Huang
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yu-Chieh Chao
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lijun Pan
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hui Zhu
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yanhua Zhao
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Weifeng Yu
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Peiying Li
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Vaamonde-García C, López-Armada MJ. Role of mitochondrial dysfunction on rheumatic diseases. Biochem Pharmacol 2019; 165:181-195. [DOI: 10.1016/j.bcp.2019.03.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 03/07/2019] [Indexed: 02/09/2023]
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Chu Q, Ding Y, Cai W, Liu L, Zhang H, Song J. Marek's Disease Virus Infection Induced Mitochondria Changes in Chickens. Int J Mol Sci 2019; 20:ijms20133150. [PMID: 31252692 PMCID: PMC6651546 DOI: 10.3390/ijms20133150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/24/2019] [Accepted: 06/26/2019] [Indexed: 11/16/2022] Open
Abstract
Mitochondria are crucial cellular organelles in eukaryotes and participate in many cell processes including immune response, growth development, and tumorigenesis. Marek’s disease (MD), caused by an avian alpha-herpesvirus Marek’s disease virus (MDV), is characterized with lymphomas and immunosuppression. In this research, we hypothesize that mitochondria may play roles in response to MDV infection. To test it, mitochondrial DNA (mtDNA) abundance and gene expression in immune organs were examined in two well-defined and highly inbred lines of chickens, the MD-susceptible line 72 and the MD-resistant line 63. We found that mitochondrial DNA contents decreased significantly at the transformation phase in spleen of the MD-susceptible line 72 birds in contrast to the MD-resistant line 63. The mtDNA-genes and the nucleus-genes relevant to mtDNA maintenance and transcription, however, were significantly up-regulated. Interestingly, we found that POLG2 might play a potential role that led to the imbalance of mtDNA copy number and gene expression alteration. MDV infection induced imbalance of mitochondrial contents and gene expression, demonstrating the indispensability of mitochondria in virus-induced cell transformation and subsequent lymphoma formation, such as MD development in chicken. This is the first report on relationship between virus infection and mitochondria in chicken, which provides important insights into the understanding on pathogenesis and tumorigenesis due to viral infection.
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Affiliation(s)
- Qin Chu
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100094, China
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20740, USA
| | - Yi Ding
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20740, USA
| | - Wentao Cai
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20740, USA
| | - Lei Liu
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20740, USA
| | - Huanmin Zhang
- USDA, Agriculture Research Service, Avian Disease and Oncology Laboratory, East Lansing, MI 48823, USA
| | - Jiuzhou Song
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20740, USA.
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38
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Inflammation research sails through the sea of immunology to reach immunometabolism. Int Immunopharmacol 2019; 73:128-145. [PMID: 31096130 DOI: 10.1016/j.intimp.2019.05.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 04/18/2019] [Accepted: 05/01/2019] [Indexed: 02/08/2023]
Abstract
Inflammation occurs as a result of acute trauma, invasion of the host by different pathogens, pathogen-associated molecular patterns (PAMPs) or chronic cellular stress generating damage-associated molecular patterns (DAMPs). Thus inflammation may occur under both sterile inflammatory conditions including certain cancers, autoimmune or autoinflammatory diseases (Rheumatic arthritis (RA)) and infectious diseases including sepsis, pneumonia-associated acute lung inflammation (ALI) or acute respiratory distress syndrome (ARDS). The pathogenesis of inflammation involves dysregulation of an otherwise protective immune response comprising of various innate and adaptive immune cells and humoral (cytokines and chemokines) mediators secreted by these immune cells upon the activation of signaling mechanisms regulated by the activation of different pattern recognition receptors (PRRs). However, the pro-inflammatory and anti-inflammatory action of these immune cells is determined by the metabolic stage of the immune cells. The metabolic process of immune cells is called immunometabolism and its shift determined by inflammatory stimuli is called immunometabolic reprogramming. The article focuses on the involvement of various immune cells generating the inflammation, their interaction, immunometabolic reprogramming, and the therapeutic targeting of the immunometabolism to manage inflammation.
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Vaz C, Reales-Calderon JA, Pitarch A, Vellosillo P, Trevisan M, Hernáez ML, Monteoliva L, Gil C. Enrichment of ATP Binding Proteins Unveils Proteomic Alterations in Human Macrophage Cell Death, Inflammatory Response, and Protein Synthesis after Interaction with Candida albicans. J Proteome Res 2019; 18:2139-2159. [PMID: 30985132 DOI: 10.1021/acs.jproteome.9b00032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Macrophages are involved in the primary human response to Candida albicans. After pathogen recognition, signaling pathways are activated, leading to the production of cytokines, chemokines, and antimicrobial peptides. ATP binding proteins are crucial for this regulation. Here, a quantitative proteomic and phosphoproteomic approach was carried out for the study of human macrophage ATP-binding proteins after interaction with C. albicans. From a total of 547 nonredundant quantified proteins, 137 were ATP binding proteins and 59 were detected as differentially abundant. From the differentially abundant ATP-binding proteins, 6 were kinases (MAP2K2, SYK, STK3, MAP3K2, NDKA, and SRPK1), most of them involved in signaling pathways. Furthermore, 85 phosphopeptides were quantified. Macrophage proteomic alterations including an increase of protein synthesis with a consistent decrease in proteolysis were observed. Besides, macrophages showed changes in proteins of endosomal trafficking together with mitochondrial proteins, including some involved in the response to oxidative stress. Regarding cell death mechanisms, an increase of antiapoptotic over pro-apoptotic signals is suggested. Furthermore, a high pro-inflammatory response was detected, together with no upregulation of key mi-RNAs involved in the negative feedback of this response. These findings illustrate a strategy to deepen the knowledge of the complex interactions between the host and the clinically important pathogen C. albicans.
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Affiliation(s)
- Catarina Vaz
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain.,Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS , 28034 Madrid , Spain
| | - Jose Antonio Reales-Calderon
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain.,Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS , 28034 Madrid , Spain
| | - Aida Pitarch
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain.,Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS , 28034 Madrid , Spain
| | - Perceval Vellosillo
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain
| | - Marco Trevisan
- Laboratorio de Proteómica Cardiovascular , Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) , 28029 Madrid , Spain
| | - María Luisa Hernáez
- Unidad de Proteómica , Universidad Complutense de Madrid , 28040 Madrid , Spain
| | - Lucía Monteoliva
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain.,Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS , 28034 Madrid , Spain
| | - Concha Gil
- Departamento de Microbiologı́a y Parasitología, Facultad de Farmacia , Universidad Complutense de Madrid , 28040 Madrid , Spain.,Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS , 28034 Madrid , Spain.,Unidad de Proteómica , Universidad Complutense de Madrid , 28040 Madrid , Spain
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40
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Paolicelli RC, Angiari S. Microglia immunometabolism: From metabolic disorders to single cell metabolism. Semin Cell Dev Biol 2019; 94:129-137. [PMID: 30954657 DOI: 10.1016/j.semcdb.2019.03.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/01/2019] [Accepted: 03/29/2019] [Indexed: 12/16/2022]
Abstract
Since the observation that obesity-associated low-grade chronic inflammation is a crucial driver for the onset of systemic metabolic disorders such as type 2 diabetes, a number of studies have highlighted the role of both the innate and the adaptive immune system in such pathologies. Moreover, researchers have recently demonstrated that immune cells can modulate their intracellular metabolic profile to control their activation and effector functions. These discoveries represent the foundations of a research area known as "immunometabolism", an emerging field of investigation that may lead to the development of new-generation therapies for the treatment of inflammatory and metabolic diseases. Most of the studies in the field have focused their attention on both circulating white blood cells and leukocytes residing within metabolic tissues such as adipose tissue, liver and pancreas. However, immunometabolism of immune cells in non-metabolic tissues, including central nervous system microglia, have long been neglected. In this review, we highlight the most recent findings suggesting that microglial cells play a central role in metabolic disorders and that interfering with the metabolic profile of microglia can modulate their functionality and pathogenicity in neurological diseases.
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Affiliation(s)
- Rosa C Paolicelli
- Department of Physiology, University of Lausanne, Rue du Bugnon 7, 1005 Lausanne, Switzerland.
| | - Stefano Angiari
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, D02 R590, Dublin, Ireland.
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Abstract
Metabolic reprograming controlling macrophage activation and function is emerging as new regulatory circuit on shaping immune responses. Generally, lipopolysaccharides (LPS)-induced pro-inflammatory activated macrophages, known as M1 macrophages, display higher glycolysis. In contrast, interleukin-4 (IL-4)-skewed anti-inflammatory activated macrophages, known as M2 macrophages, mainly rely on oxidative phosphorylation for their bioenergetic demands. Emerging evidence reveals that these metabolic preferences further fine-tune macrophage polarization process, including signaling cascades and epigenetic reprogramming. Thus, specific nutrient microenvironments may affect inflammatory responses of macrophages by intervening these metabolic machineries. How to measure the metabolic switch of macrophages both in vitro and in vivo is an important issue for understanding immunometabolic regulations in macrophages. Here, we describe a basic protocol for examining how glutamine metabolism affects macrophage polarization by using the Extracellular Flux (XF(e)96) Analyzer (Seahorse Bioscience), which takes real-time measurements of oxidative phosphorylation and glycolysis. We also present a detailed procedure for detecting the expression of inflammatory genes in polarized macrophages under glutamine-replete or -deprived conditions.
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Kumar V. Targeting macrophage immunometabolism: Dawn in the darkness of sepsis. Int Immunopharmacol 2018; 58:173-185. [PMID: 29625385 DOI: 10.1016/j.intimp.2018.03.005] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/04/2018] [Accepted: 03/05/2018] [Indexed: 12/21/2022]
Abstract
Sepsis is known since the time (470 BC) of great Greek physician, Hippocrates. Advancement in modern medicine and establishment of separate branches of medical science dealing with sepsis research have improved its outcome. However, mortality associated with sepsis still remains higher (25-30%) that further increases to 40-50% in the presence of septic shock. For example, sepsis-associated deaths account more in comparison to deaths-associated with myocardial-infarction and certain cancers (i.e. breast and colorectal cancer). However, it is now well established that profound activation of innate immune cells including macrophages play a very important role in the immunopathogenesis of sepsis. Macrophages are sentinel cells of the innate immune system with their location varying from peripheral blood to various target organs including lungs, liver, brain, kidneys, skin, testes, vascular endothelium etc. Thus, profound and dysregulated activation of these cells during sepsis can directly impact the outcome of sepsis. However, the emergence of the concept of immunometabolism as a major controller of immune response has raised a new hope for identifying new targets for immunomodulatory therapeutic approaches. Thus this present review starts with an introduction of sepsis as a major medical problem worldwide and signifies the role of dysregulated innate immune response including macrophages in its immunopathogenesis. Thereafter, subsequent sections describe changes in immunometabolic stage of macrophages (both M1 and M2) during sepsis. The article ends with the discussion of novel macrophage-specific therapeutic targets targeting their immunometabolism during sepsis and epigenetic regulation of macrophage immunometabolism and vice versa.
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Affiliation(s)
- V Kumar
- Children's Health Queensland Clinical Unit, School of Clinical Medicine, Mater Research, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia.
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