Mitochondrial Dysfunction and Immune Dysregulation in Primary Sjogren's Syndrome: Implications for Therapeutic Strategies

Anastasia V. Poznyak ¹*, Nikolay A. Orekhov ³, Dmitry Felixovich Beloyartsev ⁵, Alexey V. Churov ^3,6, Tatiana Ivanovna Kovyanova ^1,3, Irina Alexandrovna Starodubtseva ⁴,  Vasily N. Sukhorukov ³, Alexander N. Orekhov ³

Understanding how mitochondrial dysfunction contributes to immune dysregulation in Sjögren’s Syndrome may lead to new treatment strategies targeting mitochondrial function and immune responses.

Abstract

Primary Sjogren's syndrome (SjS) is a complex autoimmune disorder characterized by dry eye syndrome, xerostomia, and systemic manifestations, significantly impacting patients' quality of life. Increasing evidence suggests that immune system dysfunction and chronic inflammation play a key role in the pathogenesis of primary SjS. Recent research has highlighted the involvement of mitochondrial dysfunction and its impact on the immune microenvironment of salivary glands in primary SjS. Mitochondria, essential for cellular homeostasis, are implicated in the production of reactive oxygen species, which have been associated with the pathogenesis of primary SjS. This review article comprehensively assesses the role of mitochondria in the immune dysregulation underlying primary SjS. It delves into the molecular and cellular mechanisms linking mitochondrial dysfunction to the pathogenesis of the disorder, discussing findings from gene expression studies, mitochondrial dynamics, and metabolic pathways in different immune cell populations in salivary glands. Notably, the exploration of mitochondrial DNA copy numbers in peripheral blood mononuclear cells of primary SjS subjects provides insights into the potential impact of oxidative stress and mitochondrial function in disease development. The article also discusses potential therapeutic implications, emphasizing the importance of preserving normal mitochondrial function as a promising intervention strategy for primary SjS. Furthermore, it highlights the need for further research using advanced genomic and functional approaches to validate and expand on these findings, with the goal of identifying novel therapeutic targets and advancing our understanding of the complex interplay between mitochondrial dysfunction and immune dysregulation in primary SjS.

Keywords: Primary Sjögren’s Syndrome, Mitochondrial Dysfunction, Immune Microenvironment, Oxidative Stress, Autoimmune Disorders

References

Aderinto, N., Abdulbasit, M. O., Tangmi, A. D. E., Okesanya, J. O., & Mubarak, J. M. (2023). Unveiling the growing significance of metabolism in modulating immune cell function: exploring mechanisms and implications; a review. Annals of medicine and surgery (2012), 85(11), 5511–5522. https://doi.org/10.1097/MS9.0000000000001308

Alonso-Moreda, N., Berral-González, A., De La Rosa, E., González-Velasco, O., Sánchez-Santos, J. M., & De Las Rivas, J. (2023). Comparative Analysis of Cell Mixtures Deconvolution and Gene Signatures Generated for Blood, Immune and Cancer Cells. International journal of molecular sciences, 24(13), 10765. https://doi.org/10.3390/ijms241310765

André, F., & Böckle, B. C. (2022). Sjögren's syndrome. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 20(7), 980–1002. https://doi.org/10.1111/ddg.14823

Balasubramanian, S., Jansen, M., Valerius, M. T., Humphreys, B. D., & Strom, T. B. (2012). Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis. Journal of the American Society of Nephrology : JASN, 23(4), 674–686. https://doi.org/10.1681/ASN.2011070646

Barrera, M. J., Aguilera, S., Castro, I., Carvajal, P., Jara, D., Molina, C., González, S., & González, M. J. (2021). Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role in Sjögren's syndrome. Autoimmunity reviews, 20(8), 102867. https://doi.org/10.1016/j.autrev.2021.102867

Barrera, M. J., Aguilera, S., Castro, I., Cortés, J., Bahamondes, V., Quest, A. F. G., Molina, C., González, S., Hermoso, M., Urzúa, U., Leyton, C., & González, M. J. (2016). Pro-inflammatory cytokines enhance ERAD and ATF6α pathway activity in salivary glands of Sjögren's syndrome patients. Journal of autoimmunity, 75, 68–81. https://doi.org/10.1016/j.jaut.2016.07.006

Benchabane, S., Sour, S., Zidi, S., Hadjimi, Z., Nabila, L., Acheli, D., Bouzenad, A., Belguendouz, H., & Touil-Boukoffa, C. (2024). Exploring the relationship between oxidative stress status and inflammatory markers during primary Sjögren's syndrome: A new approach for patient monitoring. International journal of immunopathology and pharmacology, 38, 3946320241263034. https://doi.org/10.1177/03946320241263034

Blagov, A. V., Grechko, A. V., Nikiforov, N. G., Borisov, E. E., Sadykhov, N. K., & Orekhov, A. N. (2022). Role of Impaired Mitochondrial Dynamics Processes in the Pathogenesis of Alzheimer's Disease. International journal of molecular sciences, 23(13), 6954. https://doi.org/10.3390/ijms23136954

Buntenbroich, I., Anton, V., Perez-Hernandez, D., Simões, T., Gaedke, F., Schauss, A., Dittmar, G., Riemer, J., & Escobar-Henriques, M. (2023). Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target. iScience, 26(7), 107014. https://doi.org/10.1016/j.isci.2023.107014

Checa, J., & Aran, J. M. (2020). Reactive Oxygen Species: Drivers of Physiological and Pathological Processes. Journal of inflammation research, 13, 1057–1073. https://doi.org/10.2147/JIR.S275595

Chen, W., Zhao, H., & Li, Y. (2023). Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal transduction and targeted therapy, 8(1), 333. https://doi.org/10.1038/s41392-023-01547-9

Chew, V., Toh, H. C., & Abastado, J. P. (2012). Immune microenvironment in tumor progression: characteristics and challenges for therapy. Journal of oncology, 2012, 608406. https://doi.org/10.1155/2012/608406

Corona-Meraz, F. I., Vázquez-Del Mercado, M., Sandoval-García, F., Robles-De Anda, J. A., Tovar-Cuevas, A. J., Rosales-Gómez, R. C., Guzmán-Ornelas, M. O., González-Inostroz, D., Peña-Nava, M., & Martín-Márquez, B. T. (2024). Biomarkers in Systemic Lupus Erythematosus along with Metabolic Syndrome. Journal of clinical medicine, 13(7), 1988. https://doi.org/10.3390/jcm13071988

Czegle, I., Huang, C., Soria, P. G., Purkiss, D. W., Shields, A., & Wappler-Guzzetta, E. A. (2023). The Role of Genetic Mutations in Mitochondrial-Driven Cancer Growth in Selected Tumors: Breast and Gynecological Malignancies. Life (Basel, Switzerland), 13(4), 996. https://doi.org/10.3390/life13040996

De Benedittis, G., Latini, A., Colafrancesco, S., Priori, R., Perricone, C., Novelli, L., Borgiani, P., & Ciccacci, C. (2022). Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome. Biomedicines, 10(11), 2699. https://doi.org/10.3390/biomedicines10112699

Ellzey, L. M., Patrick, K. L., & Watson, R. O. (2023). Mitochondrial reactive oxygen species: double agents in Mycobacterium tuberculosis infection. Current opinion in immunology, 84, 102366. https://doi.org/10.1016/j.coi.2023.102366

Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018). Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circulation research, 122(6), 877–902. https://doi.org/10.1161/CIRCRESAHA.117.311401

Fuentes-Retamal, S., Sandoval-Acuña, C., Peredo-Silva, L., Guzmán-Rivera, D., Pavani, M., Torrealba, N., Truksa, J., Castro-Castillo, V., Catalán, M., Kemmerling, U., Urra, F. A., & Ferreira, J. (2020). Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells. Cells, 9(2), 407. https://doi.org/10.3390/cells9020407

Ganel, L., Chen, L., Christ, R., Vangipurapu, J., Young, E., Das, I., Kanchi, K., Larson, D., Regier, A., Abel, H., Kang, C. J., Scott, A., Havulinna, A., Chiang, C. W. K., Service, S., Freimer, N., Palotie, A., Ripatti, S., Kuusisto, J., Boehnke, M., … Hall, I. M. (2021). Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences. Human genomics, 15(1), 34. https://doi.org/10.1186/s40246-021-00335-2

Giamogante, F., Barazzuol, L., Brini, M., & Calì, T. (2020). ER-Mitochondria Contact Sites Reporters: Strengths and Weaknesses of the Available Approaches. International journal of molecular sciences, 21(21), 8157. https://doi.org/10.3390/ijms21218157

Goh, X. X., Tang, P. Y., & Tee, S. F. (2021). 8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis. Psychiatry investigation, 18(7), 603–618. https://doi.org/10.30773/pi.2020.0417

Gong, H., Qiu, X., Li, P., Zhao, R., Wang, B., Zhu, L., & Huo, X. (2023). Immune infiltration analysis reveals immune cell signatures in salivary gland tissue of primary Sjögren's syndrome. Frontiers in medicine, 10, 1033232. https://doi.org/10.3389/fmed.2023.1033232

Green, A., Hossain, T., & Eckmann, D. M. (2022). Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission. Frontiers in cell and developmental biology, 10, 1010232. https://doi.org/10.3389/fcell.2022.1010232

Guaragnella, N., Coyne, L. P., Chen, X. J., & Giannattasio, S. (2018). Mitochondria-cytosol-nucleus crosstalk: learning from Saccharomyces cerevisiae. FEMS yeast research, 18(8), foy088. https://doi.org/10.1093/femsyr/foy088

Hall, A. R., Burke, N., Dongworth, R. K., & Hausenloy, D. J. (2014). Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. British journal of pharmacology, 171(8), 1890–1906. https://doi.org/10.1111/bph.12516

Hayashi T. (2011). Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model. Journal of biomedicine & biotechnology, 2011, 407031. https://doi.org/10.1155/2011/407031

Hayden M. R. (2022). The Mighty Mitochondria Are Unifying Organelles and Metabolic Hubs in Multiple Organs of Obesity, Insulin Resistance, Metabolic Syndrome, and Type 2 Diabetes: An Observational Ultrastructure Study. International journal of molecular sciences, 23(9), 4820. https://doi.org/10.3390/ijms23094820

Kang, I., Chu, C. T., & Kaufman, B. A. (2018). The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS letters, 592(5), 793–811. https://doi.org/10.1002/1873-3468.12989

Kim, H., Subbannayya, Y., Humphries, F., Skejsol, A., Pinto, S. M., Giambelluca, M., Espevik, T., Fitzgerald, K. A., & Kandasamy, R. K. (2021). UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis. PloS one, 16(10), e0258989. https://doi.org/10.1371/journal.pone.0258989

Kornfeld, O. S., Qvit, N., Haileselassie, B., Shamloo, M., Bernardi, P., & Mochly-Rosen, D. (2018). Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo. Scientific reports, 8(1), 14034. https://doi.org/10.1038/s41598-018-32228-1

Kotsifaki, A., Alevizopoulos, N., Dimopoulou, V., & Armakolas, A. (2023). Unveiling the Immune Microenvironment's Role in Breast Cancer: A Glimpse into Promising Frontiers. International journal of molecular sciences, 24(20), 15332. https://doi.org/10.3390/ijms242015332

Leal, N. S., & Martins, L. M. (2021). Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines, 9(2), 227. https://doi.org/10.3390/biomedicines9020227

Li, L., Cai, D., Zhong, H., Liu, F., Jiang, Q., Liang, J., Li, P., Song, Y., Ji, A., Jiao, W., Song, J., Li, J., Chen, Z., Li, Q., & Ke, L. (2022). Mitochondrial dynamics and biogenesis indicators may serve as potential biomarkers for diagnosis of myasthenia gravis. Experimental and therapeutic medicine, 23(4), 307. https://doi.org/10.3892/etm.2022.11236

Li, N., Li, Y., Hu, J., Wu, Y., Yang, J., Fan, H., Li, L., Luo, D., Ye, Y., Gao, Y., Xu, H., Hai, W., & Jiang, L. (2022). A Link Between Mitochondrial Dysfunction and the Immune Microenvironment of Salivary Glands in Primary Sjogren's Syndrome. Frontiers in immunology, 13, 845209. https://doi.org/10.3389/fimmu.2022.845209

Lin, Y., Yan, S., Chang, X., Qi, X., & Chi, X. (2022). The global integrative network: integration of signaling and metabolic pathways. aBIOTECH, 3(4), 281–291. https://doi.org/10.1007/s42994-022-00078-1

Mikhed, Y., Daiber, A., & Steven, S. (2015). Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction. International journal of molecular sciences, 16(7), 15918–15953. https://doi.org/10.3390/ijms160715918

Mohammadnezhad, L., Shekarkar Azgomi, M., La Manna, M. P., Sireci, G., Rizzo, C., Badami, G. D., Tamburini, B., Dieli, F., Guggino, G., & Caccamo, N. (2022). Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity. Cells, 11(10), 1663. https://doi.org/10.3390/cells11101663

Negrini, S., Emmi, G., Greco, M., Borro, M., Sardanelli, F., Murdaca, G., Indiveri, F., & Puppo, F. (2022). Sjögren's syndrome: a systemic autoimmune disease. Clinical and experimental medicine, 22(1), 9–25. https://doi.org/10.1007/s10238-021-00728-6

Nesci, S., Spagnoletta, A., & Oppedisano, F. (2023). Inflammation, Mitochondria and Natural Compounds Together in the Circle of Trust. International journal of molecular sciences, 24(7), 6106. https://doi.org/10.3390/ijms24076106

Paardekooper, L. M., Vos, W., & van den Bogaart, G. (2019). Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget, 10(8), 883–896. https://doi.org/10.18632/oncotarget.26608

Pagano, G., Castello, G., & Pallardó, F. V. (2013). Sjøgren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects for chemoprevention trials. Free radical research, 47(2), 71–73. https://doi.org/10.3109/10715762.2012.748904

Park, S. Y., Oh, I. Y., Kim, J. H., Kim, H. J., Seo, B., Kwon, O. Y., Song, W. J., Kwon, H. S., Cho, Y. S., Moon, H. B., & Kim, T. B. (2020). Therapeutic Effects of Mesenchymal Stem Cells on a Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Model. Journal of Korean medical science, 35(15), e130. https://doi.org/10.3346/jkms.2020.35.e130

Park, Y. S., Gauna, A. E., & Cha, S. (2015). Mouse Models of Primary Sjogren's Syndrome. Current pharmaceutical design, 21(18), 2350–2364. https://doi.org/10.2174/1381612821666150316120024

Pontarini, E., Sciacca, E., Grigoriadou, S., Rivellese, F., Lucchesi, D., Fossati-Jimack, L., Coleby, R., Chowdhury, F., Calcaterra, F., Tappuni, A., Lewis, M. J., Fabris, M., Quartuccio, L., Bella, S. D., Bowman, S., Pitzalis, C., Mavilio, D., De Vita, S., & Bombardieri, M. (2021). NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment. Frontiers in immunology, 12, 706737. https://doi.org/10.3389/fimmu.2021.706737

Qi, Y., Yan, L., Yu, C., Guo, X., Zhou, X., Hu, X., Huang, X., Rao, Z., Lou, Z., & Hu, J. (2016). Structures of human mitofusin 1 provide insight into mitochondrial tethering. The Journal of cell biology, 215(5), 621–629. https://doi.org/10.1083/jcb.201609019

Qian, L., Zhu, Y., Deng, C., Liang, Z., Chen, J., Chen, Y., Wang, X., Liu, Y., Tian, Y., & Yang, Y. (2024). Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. Signal transduction and targeted therapy, 9(1), 50. https://doi.org/10.1038/s41392-024-01756-w

Ranieri, M., Brajkovic, S., Riboldi, G., Ronchi, D., Rizzo, F., Bresolin, N., Corti, S., & Comi, G. P. (2013). Mitochondrial fusion proteins and human diseases. Neurology research international, 2013, 293893. https://doi.org/10.1155/2013/293893

Ren, L., Chen, X., Chen, X., Li, J., Cheng, B., & Xia, J. (2020). Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells. Frontiers in cell and developmental biology, 8, 580070. https://doi.org/10.3389/fcell.2020.580070

Rocchi, C., Barazzuol, L., & Coppes, R. P. (2021). The evolving definition of salivary gland stem cells. NPJ Regenerative medicine, 6(1), 4. https://doi.org/10.1038/s41536-020-00115-x

Rossmann, M. P., Dubois, S. M., Agarwal, S., & Zon, L. I. (2021). Mitochondrial function in development and disease. Disease models & mechanisms, 14(6), dmm048912. https://doi.org/10.1242/dmm.048912

Saadi, W., Kermezli, Y., Dao, L. T. M., Mathieu, E., Santiago-Algarra, D., Manosalva, I., Torres, M., Belhocine, M., Pradel, L., Loriod, B., Aribi, M., Puthier, D., & Spicuglia, S. (2019). A critical regulator of Bcl2 revealed by systematic transcript discovery of lncRNAs associated with T-cell differentiation. Scientific reports, 9(1), 4707. https://doi.org/10.1038/s41598-019-41247-5

Seo, B. J., Choi, J., La, H., Habib, O., Choi, Y., Hong, K., & Do, J. T. (2020). Role of mitochondrial fission-related genes in mitochondrial morphology and energy metabolism in mouse embryonic stem cells. Redox biology, 36, 101599. https://doi.org/10.1016/j.redox.2020.101599

Serasinghe, M. N., & Chipuk, J. E. (2017). Mitochondrial Fission in Human Diseases. Handbook of experimental pharmacology, 240, 159–188. https://doi.org/10.1007/164_2016_38

ShilinLi, & Hu, Y. (2024). Identification of four mitochondria-related genes in sepsis based on RNA sequencing technology. BMC immunology, 25(1), 32. https://doi.org/10.1186/s12865-024-00623-1

Sidarala, V., Zhu, J., Levi-D'Ancona, E., Pearson, G. L., Reck, E. C., Walker, E. M., Kaufman, B. A., & Soleimanpour, S. A. (2022). Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis. Nature communications, 13(1), 2340. https://doi.org/10.1038/s41467-022-29945-7

Souza, P. B., de Araujo Borba, L., Castro de Jesus, L., Valverde, A. P., Gil-Mohapel, J., & Rodrigues, A. L. S. (2023). Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise. International journal of molecular sciences, 24(23), 16870. https://doi.org/10.3390/ijms242316870

Stein, J., Walkenfort, B., Cihankaya, H., Hasenberg, M., Bader, V., Winklhofer, K. F., Röderer, P., Matschke, J., Theiss, C., & Matschke, V. (2021). Increased ROS-Dependent Fission of Mitochondria Causes Abnormal Morphology of the Cell Powerhouses in a Murine Model of Amyotrophic Lateral Sclerosis. Oxidative medicine and cellular longevity, 2021, 6924251. https://doi.org/10.1155/2021/6924251

Sun, J. X., Xu, X. H., & Jin, L. (2022). Effects of Metabolism on Macrophage Polarization Under Different Disease Backgrounds. Frontiers in immunology, 13, 880286. https://doi.org/10.3389/fimmu.2022.880286

Sundaresan, B., Shirafkan, F., Ripperger, K., & Rattay, K. (2023). The Role of Viral Infections in the Onset of Autoimmune Diseases. Viruses, 15(3), 782. https://doi.org/10.3390/v15030782

Urzì, O., Gasparro, R., Costanzo, E., De Luca, A., Giavaresi, G., Fontana, S., & Alessandro, R. (2023). Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models. International journal of molecular sciences, 24(15), 12046. https://doi.org/10.3390/ijms241512046

Vacca, R. A., Valenti, D., Bobba, A., Merafina, R. S., Passarella, S., & Marra, E. (2006). Cytochrome c is released in a reactive oxygen species-dependent manner and is degraded via caspase-like proteases in tobacco Bright-Yellow 2 cells en route to heat shock-induced cell death. Plant physiology, 141(1), 208–219. https://doi.org/10.1104/pp.106.078683

Verstappen, G. M., Pringle, S., Bootsma, H., & Kroese, F. G. M. (2021). Epithelial-immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis. Nature reviews. Rheumatology, 17(6), 333–348. https://doi.org/10.1038/s41584-021-00605-2

Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019). The Metabolic Signature of Macrophage Responses. Frontiers in immunology, 10, 1462. https://doi.org/10.3389/fimmu.2019.01462

Wang, H., Zhang, J., He, C., Peng, F., Liu, Z., & Xiao, D. (2022). Plasma Cell Myeloma Mimicking Metastatic Carcinoma with CD138 positivity: a Potential Diagnostic Pitfall. Clinical laboratory, 68(3), 10.7754/Clin.Lab.2021.210635. https://doi.org/10.7754/Clin.Lab.2021.210635

Wang, X. B., Cui, N. H., Liu, X., & Liu, X. (2020). Mitochondrial 8-hydroxy-2'-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus. Cardiovascular diabetology, 19(1), 22. https://doi.org/10.1186/s12933-020-00998-6

Wang, Y., Huang, Z., Xiao, Y., Wan, W., & Yang, X. (2022). The shared biomarkers and pathways of systemic lupus erythematosus and metabolic syndrome analyzed by bioinformatics combining machine learning algorithm and single-cell sequencing analysis. Frontiers in immunology, 13, 1015882. https://doi.org/10.3389/fimmu.2022.1015882

Xiang, Y., Zhang, M., Jiang, D., Su, Q., & Shi, J. (2023). The role of inflammation in autoimmune disease: a therapeutic target. Frontiers in immunology, 14, 1267091. https://doi.org/10.3389/fimmu.2023.1267091

Xiao, S., Li, S., Yuan, Z., & Zhou, L. (2020). Pyrroline-5-carboxylate reductase 1 (PYCR1) upregulation contributes to gastric cancer progression and indicates poor survival outcome. Annals of translational medicine, 8(15), 937. https://doi.org/10.21037/atm-19-4402

Xu, Y., Xue, D., Bankhead, A., 3rd, & Neamati, N. (2020). Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?. Journal of medicinal chemistry, 63(23), 14276–14307. https://doi.org/10.1021/acs.jmedchem.0c01013

Yarosz, E. L., & Chang, C. H. (2018). The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease. Immune network, 18(1), e14. https://doi.org/10.4110/in.2018.18.e14

Yu, X., Chen, Y. A., Conejo-Garcia, J. R., Chung, C. H., & Wang, X. (2019). Estimation of immune cell content in tumor using single-cell RNA-seq reference data. BMC cancer, 19(1), 715. https://doi.org/10.1186/s12885-019-5927-3

Zaripova, L. N., Midgley, A., Christmas, S. E., Beresford, M. W., Pain, C., Baildam, E. M., & Oldershaw, R. A. (2023). Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. International journal of molecular sciences, 24(22), 16040. https://doi.org/10.3390/ijms242216040

Zhang, Z., Yang, D., Zhou, B., Luan, Y., Yao, Q., Liu, Y., Yang, S., Jia, J., Xu, Y., Bie, X., Wang, Y., Li, Z., Li, A., Zheng, H., & He, Y. (2022). Decrease of MtDNA copy number affects mitochondrial function and involves in the pathological consequences of ischaemic stroke. Journal of cellular and molecular medicine, 26(15), 4157–4168. https://doi.org/10.1111/jcmm.17262

Zheng, Q., Liu, L., Wang, B., He, Y., Zhang, M., & Shi, G. (2023). Phosphorylated signal transducer and activator of transcription proteins 1 in salivary glandular tissue: an important histological marker for diagnosis of primary Sjögren's syndrome. RMD open, 9(1), e002694. https://doi.org/10.1136/rmdopen-2022-002694

Zheng, Y., Yao, Y., Ge, T., Ge, S., Jia, R., Song, X., & Zhuang, A. (2023). Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity. Journal of experimental & clinical cancer research : CR, 42(1), 291. https://doi.org/10.1186/s13046-023-02845-4

Zimmerman, D., & Dang, N. H. (2019). Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): Immunologic Reactions. Oncologic Critical Care, 267–280. https://doi.org/10.1007/978-3-319-74588-6_195