{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:56:15Z","timestamp":1792551375790,"version":"4.5.0"},"reference-count":125,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014NextGenerationEU","award":["BG-RRP-2.004-0007-C03"],"award-info":[{"award-number":["BG-RRP-2.004-0007-C03"]}]},{"award":["BG-RRP-2.004-0007-C03"],"award-info":[{"award-number":["BG-RRP-2.004-0007-C03"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"MU-Plovdiv","award":["NO15-2025"],"award-info":[{"award-number":["NO15-2025"]}]},{"award":["NO15-2025"],"award-info":[{"award-number":["NO15-2025"]}],"id":[{"id":"https:\/\/ror.org\/02kzxd152","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondria are increasingly recognized as multifunctional organelles that integrate metabolic, redox, immune, and cell fate signaling, thereby maintaining cellular and tissue homeostasis under physiological conditions. Beyond their classical role in ATP production, mitochondria act as central regulatory hubs coordinating adaptive responses to metabolic demands and environmental stress. These functions are sustained through tightly regulated quality control mechanisms, including mitochondrial biogenesis, dynamic fusion\u2013fission remodeling, redox signaling, and selective removal of damaged organelles via mitophagy. Disruption of these processes compromises cellular resilience and contributes to disease initiation and progression. This review summarizes and critically evaluates current evidence on mitochondrial function in health and its dysregulation in pathological conditions, with a particular focus on rheumatoid arthritis (RA), ischemic stroke (IS), and autism spectrum disorder (ASD). Despite their distinct clinical manifestations, these disorders share convergent mitochondrial abnormalities, including metabolic reprogramming toward glycolysis, excessive or persistent reactive oxygen species production, impaired mitophagy, mitochondrial DNA-driven innate immune activation, and hypoxia-related stress. In RA, mitochondrial dysfunction sustains chronic inflammation and joint destruction; in IS, acute mitochondrial failure and reperfusion-associated oxidative stress drive neuronal injury; and in ASD, mitochondrial metabolic inflexibility and defective quality control contribute to chronic low-grade inflammation and neurodevelopmental vulnerability. A variety of methods for the assessment of mitochondrial function are available to study these pathological conditions. Collectively, these findings position mitochondrial dysfunction as a unifying pathogenic mechanism linking inflammatory, neurodegenerative, and neurodevelopmental processes. Targeting mitochondrial metabolism, redox balance, and quality control pathways therefore represents a promising cross-disease therapeutic strategy.<\/jats:p>","DOI":"10.3390\/ijms27093871","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mitochondria as an Integrative Hub of Cellular Homeostasis and Stress Response"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3845-2072","authenticated-orcid":false,"given":"Valentina","family":"Mihaylova","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Kovacheva","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gevezova","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1501-0175","authenticated-orcid":false,"given":"Victoria","family":"Sarafian","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kazakova","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Andrieux, P., Chevillard, C., Cunha-Neto, E., and Nunes, J.P.S. (2021). Mitochondria as a Cellular Hub in Infection and Inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111338"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Guan, S., Zhao, L., and Peng, R. (2022). Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213880"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Protasoni, M., and Zeviani, M. (2021). Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020586"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bj.2017.12.001","article-title":"Structure and mechanism of mitochondrial electron transport chain","volume":"41","author":"Guo","year":"2018","journal-title":"Biomed. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement","volume":"37","author":"Braganza","year":"2020","journal-title":"Redox Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.cyto.2009.02.011","article-title":"Extracellular ATP and P2 receptors are required for IL-8 to induce neutrophil migration","volume":"46","author":"Kukulski","year":"2009","journal-title":"Cytokine"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gombault, A., Baron, L., and Couillin, I. (2012). ATP release and purinergic signaling in NLRP3 inflammasome activation. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00414"},{"key":"ref_8","first-page":"6","article-title":"Role of P2X7 Receptors in Release of IL-1beta: A Possible Mediator of Pulmonary Inflammation","volume":"11","author":"Mortaz","year":"2012","journal-title":"Tanaffos"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cmet.2012.01.015","article-title":"Mitochondrial complex I plays an essential role in human respirasome assembly","volume":"15","author":"Fontanesi","year":"2012","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tang, J.X., Thompson, K., Taylor, R.W., and Olahova, M. (2020). Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113820"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.semcancer.2022.02.002","article-title":"Targeting OXPHOS and the electron transport chain in cancer; Molecular and therapeutic implications","volume":"86","author":"Greene","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pereira, S.P., and Tavares, L.C. (2025). Beyond Powerhouses: Roles of Mitochondria, from Development to Therapeutic Potential. Biology, 14.","DOI":"10.3390\/biology14101367"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.15698\/cst2018.10.158","article-title":"Mitochondrial stress management: A dynamic journey","volume":"2","author":"Canto","year":"2018","journal-title":"Cell Stress."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kim, M.E., Lim, Y., and Lee, J.S. (2025). Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47121042"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41392-024-01839-8","article-title":"Mitochondrial dysfunction: Mechanisms and advances in therapy","volume":"9","author":"Zong","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1750-1326-6-32","article-title":"PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease","volume":"6","author":"Saft","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Green, A., Hossain, T., and Eckmann, D.M. (2022). Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1010232"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a008706","DOI":"10.1101\/cshperspect.a008706","article-title":"Mitochondrial regulation of cell death","volume":"5","author":"Tait","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41586-024-07340-0","article-title":"Mitochondrial transfer mediates endothelial cell engraftment through mitophagy","volume":"629","author":"Lin","year":"2024","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.tibs.2010.04.002","article-title":"Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes","volume":"35","author":"Hamanaka","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s10545-015-9861-5","article-title":"Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism","volume":"38","author":"Olsen","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kowalczyk, P., Sulejczak, D., Kleczkowska, P., Bukowska-Osko, I., Kucia, M., Popiel, M., Wietrak, E., Kramkowski, K., Wrzosek, K., and Kaczynska, K. (2021). Mitochondrial Oxidative Stress\u2014A Causative Factor and Therapeutic Target in Many Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413384"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1089\/ars.2015.6407","article-title":"The Roles of Mitochondrial Damage\u2014Associated Molecular Patterns in Diseases","volume":"23","author":"Nakahira","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhou, Z., Ou-Yang, C., Chen, Q., Ren, Z., Guo, X., Lei, M., Liu, C., and Yang, X. (2023). Trafficking and effect of released DNA on cGAS-STING signaling pathway and cardiovascular disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1287130"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1089\/ars.2023.0367","article-title":"Mitochondrial Mechanisms in Immunity and Inflammatory Conditions: Beyond Energy Management","volume":"41","author":"Alvarez","year":"2024","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Trinchese, G., Cimmino, F., Catapano, A., Cavaliere, G., and Mollica, M.P. (2024). Mitochondria: The gatekeepers between metabolism and immunity. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1334006"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8200","DOI":"10.1523\/JNEUROSCI.1157-19.2019","article-title":"Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease","volume":"39","author":"Rangaraju","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nesci, S., and Lenaz, G. (2022). Impaired Mitochondrial Bioenergetics under Pathological Conditions. Life, 12.","DOI":"10.3390\/life12020205"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ma, C., Wang, J., Hong, F., and Yang, S. (2022). Mitochondrial Dysfunction in Rheumatoid Arthritis. Biomolecules, 12.","DOI":"10.3390\/biom12091216"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"156300","DOI":"10.1016\/j.metabol.2025.156300","article-title":"Overview of methods that determine mitochondrial function in human disease","volume":"170","author":"Sharma","year":"2025","journal-title":"Metabolism"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7334","DOI":"10.1038\/s44318-025-00632-9","article-title":"Measuring mitochondrial membrane potential","volume":"44","author":"Rubio","year":"2025","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/978-1-4939-2257-4_14","article-title":"Simultaneous quantification of mitochondrial ATP and ROS production","volume":"1264","author":"Yu","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15038","DOI":"10.1073\/pnas.0601945103","article-title":"Selective fluorescent imaging of superoxide in vivo using ethidium-based probes","volume":"103","author":"Robinson","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nprot.2012.058","article-title":"Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells","volume":"7","author":"Spinazzi","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3892\/ijmm.2022.5182","article-title":"Common methods in mitochondrial research (Review)","volume":"50","author":"Yin","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103401","DOI":"10.1016\/j.redox.2024.103401","article-title":"Neutrophils with low production of reactive oxygen species are activated during immune priming and promote development of arthritis","volume":"78","author":"Chen","year":"2024","journal-title":"Redox Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1177\/0271678X211046992","article-title":"Mitochondrial quality control in acute ischemic stroke","volume":"41","author":"An","year":"2021","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100829","DOI":"10.1016\/j.spen.2020.100829","article-title":"Mitochondrial Dysfunction in Autism Spectrum Disorder: Unique Abnormalities and Targeted Treatments","volume":"35","author":"Frye","year":"2020","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00296-023-05501-4","article-title":"JAK inhibitors improve ATP production and mitochondrial function in rheumatoid arthritis: A pilot study","volume":"44","author":"Mihaylova","year":"2024","journal-title":"Rheumatol. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13075-017-1303-3","article-title":"Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis","volume":"19","author":"Bustamante","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1186\/ar2292","article-title":"Cells of the synovium in rheumatoid arthritis","volume":"9","author":"Otero","year":"2007","journal-title":"Chondrocytes. Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1016\/S0140-6736(23)01525-8","article-title":"Rheumatoid arthritis","volume":"402","author":"Bathon","year":"2023","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: The metabolic requirements of cell proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41420-025-02403-1","article-title":"Metabolic reprogram and T cell differentiation in inflammation: Current evidence and future perspectives","volume":"11","author":"Shi","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.coi.2017.04.010","article-title":"Metabolic signatures of T-cells and macrophages in rheumatoid arthritis","volume":"46","author":"Weyand","year":"2017","journal-title":"Curr. Opin. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1186\/s12967-025-07392-4","article-title":"Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance","volume":"23","author":"Algieri","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/art.40406","article-title":"The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine","volume":"70","author":"You","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e70268","DOI":"10.1002\/mco2.70268","article-title":"Oxidative Stress: Signaling Pathways, Biological Functions, and Disease","volume":"6","author":"Liu","year":"2025","journal-title":"MedComm (2020)"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Jing, W., Liu, C., Su, C., Liu, L., Chen, P., Li, X., Zhang, X., Yuan, B., Wang, H., and Du, X. (2023). Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1107670"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gong, X., Yang, S.Y., Wang, Z.Y., and Tang, M. (2024). The role of hypoxic microenvironment in autoimmune diseases. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1435306"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Bouhamida, E., Morciano, G., Perrone, M., Kahsay, A.E., Della Sala, M., Wieckowski, M.R., Fiorica, F., Pinton, P., Giorgi, C., and Patergnani, S. (2022). The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches. Biology, 11.","DOI":"10.3390\/biology11020300"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e13622","DOI":"10.1111\/acel.13622","article-title":"Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation","volume":"21","author":"Zhong","year":"2022","journal-title":"Aging Cell"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Iaconis, A., Molinari, F., Fusco, R., and Di Paola, R. (2025). Mitochondria as a Disease-Relevant Organelle in Rheumatoid Arthritis: A Key Breakout in Fight Against the Disease. Biomedicines, 13.","DOI":"10.3390\/biomedicines13071708"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41422-025-01203-7","article-title":"Mitophagy in the pathogenesis and management of disease","volume":"36","author":"Wang","year":"2026","journal-title":"Cell Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Nam, J.H., Lee, J.H., Choi, H.J., Choi, S.Y., Noh, K.E., Jung, N.C., Song, J.Y., Choi, J., Seo, H.G., and Jung, S.Y. (2022). TNF-alpha Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhibition Alleviates Synovitis in Collagen Antibody-Induced Arthritis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105650"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Riitano, G., Recalchi, S., Capozzi, A., Manganelli, V., Misasi, R., Garofalo, T., Sorice, M., and Longo, A. (2023). The Role of Autophagy as a Trigger of Post-Translational Modifications of Proteins and Extracellular Vesicles in the Pathogenesis of Rheumatoid Arthritis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612764"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1177\/0271678X17740091","article-title":"Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus","volume":"39","author":"Schneider","year":"2019","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Liang, J., Han, R., and Zhou, B. (2021). Metabolic Reprogramming: Strategy for Ischemic Stroke Treatment by Ischemic Preconditioning. Biology, 10.","DOI":"10.3390\/biology10050424"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12974-023-02742-9","article-title":"The critical role of KLF4 in regulating the activation of A1\/A2 reactive astrocytes following ischemic stroke","volume":"20","author":"Wang","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1038\/s41380-022-01521-x","article-title":"Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability","volume":"29","author":"Zhang","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1046\/j.1365-201X.1996.449170000.x","article-title":"Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury","volume":"156","author":"Kuroda","year":"1996","journal-title":"Acta Physiol. Scand."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature13909","article-title":"Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS","volume":"515","author":"Chouchani","year":"2014","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Shaafi, S., Hadisi, F., Mahmoudinezhad, M., Razmi, H., Nejadghaderi, S.A., and Khalili, M. (2021). The significance of the oxidative stress markers in the one-year prognosis of patients with acute ischemic stroke: A case-control study. BMC Neurol., 21.","DOI":"10.1186\/s12883-021-02257-x"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7083","DOI":"10.1523\/JNEUROSCI.1645-07.2007","article-title":"Neurovascular protection by ischemic tolerance: Role of nitric oxide and reactive oxygen species","volume":"27","author":"Kunz","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.freeradbiomed.2019.11.005","article-title":"Mitochondria as a therapeutic target for ischemic stroke","volume":"146","author":"He","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1097\/SHK.0000000000000160","article-title":"Cerebrospinal fluid mitochondrial DNA: A novel DAMP in pediatric traumatic brain injury","volume":"41","author":"Walko","year":"2014","journal-title":"Shock."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"He, Q., Li, Z., Meng, C., Wu, J., Zhao, Y., and Zhao, J. (2019). Parkin-Dependent Mitophagy is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats. Cells, 8.","DOI":"10.2139\/ssrn.3424194"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Shao, Z., Dou, S., Zhu, J., Wang, H., Xu, D., Wang, C., Cheng, B., and Bai, B. (2020). The Role of Mitophagy in Ischemic Stroke. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.608610"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.freeradbiomed.2014.01.014","article-title":"The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c","volume":"69","author":"Domazou","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.4103\/1673-5374.274331","article-title":"Autophagy and inflammation in ischemic stroke","volume":"15","author":"Mo","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7432797","DOI":"10.1155\/2016\/7432797","article-title":"Oxidative Stress and Inflammation: What Polyphenols Can Do for Us?","volume":"2016","author":"Hussain","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bbi.2022.12.001","article-title":"Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD)","volume":"108","author":"Hughes","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1542\/peds.2007-0391","article-title":"Mitochondrial disease: A practical approach for primary care physicians","volume":"120","author":"Haas","year":"2007","journal-title":"Pediatrics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41423-022-00902-0","article-title":"Redox regulation of the immune response","volume":"19","author":"Morris","year":"2022","journal-title":"Cell Mol. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/j.1469-8749.2007.00726.x","article-title":"Epidemiology of autism spectrum disorder in Portugal: Prevalence, clinical characterization, and medical conditions","volume":"49","author":"Oliveira","year":"2007","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11655","DOI":"10.1038\/s41598-023-38306-3","article-title":"Increased glutamate and glutamine levels and their relationship to astrocytes and dopaminergic transmissions in the brains of adults with autism","volume":"13","author":"Oya","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Shimmura, C., Suda, S., Tsuchiya, K.J., Hashimoto, K., Ohno, K., Matsuzaki, H., Iwata, K., Matsumoto, K., Wakuda, T., and Kameno, Y. (2011). Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025340"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e220","DOI":"10.1038\/tp.2012.143","article-title":"Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder","volume":"3","author":"Frye","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"985","DOI":"10.2174\/1568026621666210521142131","article-title":"Cellular Bioenergetic and Metabolic Changes in Patients with Autism Spectrum Disorder","volume":"21","author":"Gevezova","year":"2021","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41392-024-01954-6","article-title":"Metabolic regulation of the immune system in health and diseases: Mechanisms and interventions","volume":"9","author":"Hu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.mito.2023.04.003","article-title":"Mitochondrial and metabolic features of salugenesis and the healing cycle","volume":"70","author":"Naviaux","year":"2023","journal-title":"Mitochondrion"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2017.12.007","article-title":"Antipurinergic therapy for autism\u2014An in-depth review","volume":"43","author":"Naviaux","year":"2018","journal-title":"Mitochondrion"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/mp.2010.136","article-title":"Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis","volume":"17","author":"Rossignol","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/mp.2011.165","article-title":"A review of research trends in physiological abnormalities in autism spectrum disorders: Immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures","volume":"17","author":"Rossignol","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s10803-011-1260-7","article-title":"Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism","volume":"42","author":"Melnyk","year":"2012","journal-title":"J. Autism Dev. Disord."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1038\/tp.2013.51","article-title":"Redox metabolism abnormalities in autistic children associated with mitochondrial disease","volume":"3","author":"Frye","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5629","DOI":"10.1007\/s12035-024-04637-z","article-title":"Crosstalk Between Mitochondrial DNA and Immune Response: Focus on Autism Spectrum Disorder","volume":"62","author":"Qu","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.neuron.2014.07.040","article-title":"Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits","volume":"83","author":"Tang","year":"2014","journal-title":"Neuron"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"11348","DOI":"10.1038\/s41598-018-29421-7","article-title":"Beyond autophagy: A novel role for autism-linked Wdfy3 in brain mitophagy","volume":"8","author":"Napoli","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_90","first-page":"1","article-title":"Cross-species models of attention-deficit\/hyperactivity disorder and autism spectrum disorder: Lessons from CNTNAP2, ADGRL3, and PARK2","volume":"29","author":"Mortimer","year":"2019","journal-title":"Psychiatr. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/ana.21317","article-title":"Cognitive deficits in Tsc1+\/\u2212 mice in the absence of cerebral lesions and seizures","volume":"62","author":"Goorden","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1002\/aur.3250","article-title":"Prenatal exposure to hypoxic risk conditions in autistic and neurotypical youth: Associated ventricular differences, sleep disturbance, and sensory processing","volume":"17","author":"Preciado","year":"2024","journal-title":"Autism Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1113\/JP271402","article-title":"The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome","volume":"594","author":"Miller","year":"2016","journal-title":"J. Physiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jpsychires.2014.03.019","article-title":"Prenatal and perinatal risk factors in a twin study of autism spectrum disorders","volume":"54","author":"Cleveland","year":"2014","journal-title":"J. Psychiatr. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1080\/15548627.2019.1596497","article-title":"Mitophagy and NAD+ inhibit Alzheimer disease","volume":"15","author":"Fang","year":"2019","journal-title":"Autophagy"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1007\/s12035-017-0712-2","article-title":"From Mitochondrial Function to Neuroprotection\u2014An Emerging Role for Methylene Blue","volume":"55","author":"Tucker","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1161\/STROKEAHA.115.008921","article-title":"Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2","volume":"46","author":"Narayanan","year":"2015","journal-title":"Stroke"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s12975-016-0495-1","article-title":"Mechanisms of Axonal Damage and Repair after Central Nervous System Injury","volume":"8","author":"Egawa","year":"2017","journal-title":"Transl. Stroke Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s12975-018-0642-y","article-title":"Mitochondrial Dysfunction in Stroke: Implications of Stem Cell Therapy","volume":"10","author":"Sarmah","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.jtcvs.2017.02.018","article-title":"Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury","volume":"154","author":"Emani","year":"2017","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.cell.2014.03.026","article-title":"Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+\/SIRT1 reduction","volume":"157","author":"Fang","year":"2014","journal-title":"Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.cmet.2016.09.004","article-title":"NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair","volume":"24","author":"Fang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.molmed.2019.07.002","article-title":"Mitophagy and Neuroprotection","volume":"26","author":"Lou","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.neurobiolaging.2012.11.020","article-title":"Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: Evidence for improved neuronal bioenergetics and autophagy procession","volume":"34","author":"Liu","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.diabres.2015.10.020","article-title":"Myopia and diabetic retinopathy: A systematic review and meta-analysis","volume":"111","author":"Wang","year":"2016","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/nm.4132","article-title":"Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents","volume":"22","author":"Ryu","year":"2016","journal-title":"Nat. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s42255-019-0073-4","article-title":"The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans","volume":"1","author":"Andreux","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/s41593-018-0332-9","article-title":"Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer\u2019s disease","volume":"22","author":"Fang","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"eaan2788","DOI":"10.1126\/science.aan2788","article-title":"Spermidine in health and disease","volume":"359","author":"Madeo","year":"2018","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"17475","DOI":"10.18632\/oncotarget.15728","article-title":"Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway","volume":"8","author":"Fan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1038\/nn.3512","article-title":"Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner","volume":"16","author":"Gupta","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/ncb1975","article-title":"Induction of autophagy by spermidine promotes longevity","volume":"11","author":"Eisenberg","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/nm.4222","article-title":"Cardioprotection and lifespan extension by the natural polyamine spermidine","volume":"22","author":"Eisenberg","year":"2016","journal-title":"Nat. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"16852","DOI":"10.18632\/aging.103578","article-title":"Spermidine inhibits neurodegeneration and delays aging via the PINK1-PDR1-dependent mitophagy pathway in C. elegans","volume":"12","author":"Yang","year":"2020","journal-title":"Aging"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"46208","DOI":"10.1038\/srep46208","article-title":"Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1\/Nrf2 pathway","volume":"7","author":"Fang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1016\/j.febslet.2008.05.049","article-title":"Tomatidine inhibits iNOS and COX-2 through suppression of NF-kappaB and JNK pathways in LPS-stimulated mouse macrophages","volume":"582","author":"Chiu","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1111\/jphp.12205","article-title":"Protective effect of tomatine against hydrogen peroxide-induced neurotoxicity in neuroblastoma (SH-SY5Y) cells","volume":"66","author":"Huang","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng1362","article-title":"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease","volume":"36","author":"Ravikumar","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"605","DOI":"10.5582\/bst.2018.01263","article-title":"Protective effects of metformin against osteoarthritis through upregulation of SIRT3-mediated PINK1\/Parkin-dependent mitophagy in primary chondrocytes","volume":"12","author":"Wang","year":"2019","journal-title":"Biosci. Trends"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1111\/bph.13627","article-title":"Effects of anthocyanins on the prevention and treatment of cancer","volume":"174","author":"Lin","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4062\/biomolther.2012.20.1.068","article-title":"Anthocyanin Extracts from Black Soybean (Glycine max L.) Protect Human Glial Cells Against Oxygen-Glucose Deprivation by Promoting Autophagy","volume":"20","author":"Kim","year":"2012","journal-title":"Biomol. Ther."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"105651","DOI":"10.1016\/j.intimp.2019.05.036","article-title":"Astragaloside IV ameliorates motor deficits and dopaminergic neuron degeneration via inhibiting neuroinflammation and oxidative stress in a Parkinson\u2019s disease mouse model","volume":"75","author":"Yang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhang, Y., Jin, X.F., Zhou, X.H., Dong, X.H., Yu, W.T., and Gao, W.J. (2019). The Role of Astragaloside IV against Cerebral Ischemia\/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy. Molecules, 24.","DOI":"10.3390\/molecules24091838"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1016\/j.apsb.2020.10.018","article-title":"Natural compounds modulate the autophagy with potential implication of stroke","volume":"11","author":"Ahsan","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41536-020-00107-x","article-title":"Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation","volume":"5","author":"Norat","year":"2020","journal-title":"npj Regen. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3871\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:48:12Z","timestamp":1777376892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":125,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093871"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093871","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,27]]}}}