Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.
Συγγραφείς:	Zhang Y; School of Traditional Chinese Medicine, Yangzhou University, Yangzhou, 225003, China., Zhu J; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China., Cui L; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Chen S; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Li X; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Gao L; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Chen X; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Wen K; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China., Zeng B; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. zbb020708@163.com., Qian Y; School of Traditional Chinese Medicine, Yangzhou University, Yangzhou, 225003, China. yyqian@yzu.edu.cn.; NATCM Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer, Yangzhou, China. yyqian@yzu.edu.cn.
Πηγή:	Biogerontology [Biogerontology] 2026 Oct 03; Vol. 27 (5). Date of Electronic Publication: 2026 Oct 03.
Τύπος έκδοσης:	Journal Article; Review
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: Kluwer Academic Country of Publication: Netherlands NLM ID: 100930043 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-6768 (Electronic) Linking ISSN: 13895729 NLM ISO Abbreviation: Biogerontology Subsets: MEDLINE
Imprint Name(s):	Original Publication: Dordrecht ; Boston : Kluwer Academic, c2000-
Ιατρικοί όροι (MeSH):	DNA, Mitochondrial/metabolism , DNA, Mitochondrial/genetics , Cellular Senescence/immunology , Cellular Senescence/physiology , Mitochondria/metabolism , Mitochondria/immunology , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism, Inflammation/immunology ; Humans ; cGAS-STING Signaling Pathway ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Animals ; Homeostasis ; Signal Transduction
Περίληψη:	In addition to cell cycle arrest, cellular senescence is characterized by disrupted mitochondrial homeostasis, development of the senescence-associated secretory phenotype (SASP), and alterations in the immune microenvironment. Mitochondrial membrane damage, disrupted mitochondrial dynamics, and impaired mitochondrial quality control (MQC) can occur during cellular senescence. These changes may cause mitochondrial DNA (mtDNA) to leak abnormally into the cytosol. Cytosolic mtDNA can then activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Unlike the acute innate immune response elicited by pathogen-derived DNA, cGAS-STING signaling in senescent cells is mainly activated by the aberrant cytosolic accumulation of endogenous DNA. This signaling activates the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) axis and induces a type I interferon response. It also promotes nuclear factor kappaB (NF-κB)-mediated inflammatory transcription, sustains the SASP, and modulates paracrine signaling and immune cell function. This review focuses on mitochondrial structural damage, mtDNA release, and impaired MQC. It summarizes the mechanisms that activate the mtDNA-cGAS-STING axis during cellular senescence and examines its functional changes. It also discusses the potential development of senescence-associated biomarkers. Current evidence suggests that this signaling axis mainly contributes to the maintenance and amplification of the inflammatory senescence phenotype. It is unlikely to independently determine the onset of cellular senescence. Its effects are highly dependent on cell type and pathological context, while assay standards, causal relationships, and therapeutic windows require further clarification. (© 2026. The Author(s), under exclusive licence to Springer Nature B.V.)
Competing Interests:	Declarations. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Consent for publication: All participating authors have reviewed this paper and sanctioned its publication.
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Grant Information:	81403232 National Natural Science Foundation of China; 19KJA480003 Major Programs of Natural Science Foundation of higher education in Jiangsu Province; BK20171290 Natural Science Foundation of Jiangsu Province; BY20240547 Industry-University-Research Collaboration Project of Jiangsu Province
Contributed Indexing:	Keywords: CGAS-STING; Cellular senescence; Immunomodulation; Inflammatory senescence; Mitochondrial DNA; SASP
Substance Nomenclature:	0 (DNA, Mitochondrial) 0 (STING Protein) EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase) 0 (Membrane Proteins) 0 (STING1 protein, human) EC 2.7.7.- (Nucleotidyltransferases) EC 2.7.7.- (cGAS protein, human)
Entry Date(s):	Date Created: 20261003 Date Completed: 20261003 Latest Revision: 20261003
Update Code:	20261004
DOI:	10.1007/s10522-026-10515-z
PMID:	42828712
Βάση Δεδομένων:	MEDLINE

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Items	– Name: Title Label: Title Group: Ti Data: Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AU" term="%22Zhang+Y%22">Zhang Y</searchLink>; School of Traditional Chinese Medicine, Yangzhou University, Yangzhou, 225003, China.<br /><searchLink fieldCode="AU" term="%22Zhu+J%22">Zhu J</searchLink>; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.<br /><searchLink fieldCode="AU" term="%22Cui+L%22">Cui L</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Chen+S%22">Chen S</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Li+X%22">Li X</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Gao+L%22">Gao L</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Chen+X%22">Chen X</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Wen+K%22">Wen K</searchLink>; Faculty of Medicine, Yangzhou University, Yangzhou, 225009, China.<br /><searchLink fieldCode="AU" term="%22Zeng+B%22">Zeng B</searchLink>; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. zbb020708@163.com.<br /><searchLink fieldCode="AU" term="%22Qian+Y%22">Qian Y</searchLink>; School of Traditional Chinese Medicine, Yangzhou University, Yangzhou, 225003, China. yyqian@yzu.edu.cn.; NATCM Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer, Yangzhou, China. yyqian@yzu.edu.cn. – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22100930043%22">Biogerontology</searchLink> [Biogerontology] 2026 Oct 03; Vol. 27 (5). <i>Date of Electronic Publication: </i>2026 Oct 03. – Name: TypePub Label: Publication Type Group: TypPub Data: Journal Article; Review – Name: Language Label: Language Group: Lang Data: English – Name: TitleSource Label: Journal Info Group: Src Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Kluwer+Academic%22">Kluwer Academic </searchLink><i>Country of Publication: </i>Netherlands <i>NLM ID: </i>100930043 <i>Publication Model: </i>Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1573-6768 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2213895729%22">13895729 </searchLink><i>NLM ISO Abbreviation: </i>Biogerontology <i>Subsets: </i>MEDLINE – Name: PublisherInfo Label: Imprint Name(s) Group: PubInfo Data: <i>Original Publication</i>: Dordrecht ; Boston : Kluwer Academic, c2000- – Name: SubjectMESH Label: MeSH Terms Group: Su Data: <searchLink fieldCode="MM" term="%22DNA%2C+Mitochondrial%22">DNA, Mitochondrial</searchLink>/<searchLink fieldCode="MM" term="%22DNA%2C+Mitochondrial+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22DNA%2C+Mitochondrial%22">DNA, Mitochondrial</searchLink>/<searchLink fieldCode="MM" term="%22DNA%2C+Mitochondrial+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellular+Senescence%22">Cellular Senescence</searchLink>/<searchLink fieldCode="MM" term="%22Cellular+Senescence+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellular+Senescence%22">Cellular Senescence</searchLink>/<searchLink fieldCode="MM" term="%22Cellular+Senescence+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Mitochondria%22">Mitochondria</searchLink>/<searchLink fieldCode="MM" term="%22Mitochondria+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Mitochondria%22">Mitochondria</searchLink>/<searchLink fieldCode="MM" term="%22Mitochondria+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Membrane+Proteins%22">Membrane Proteins</searchLink>/<searchLink fieldCode="MM" term="%22Membrane+Proteins+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Nucleotidyltransferases%22">Nucleotidyltransferases</searchLink>/<searchLink fieldCode="MM" term="%22Nucleotidyltransferases+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Inflammation%22">Inflammation</searchLink>/<searchLink fieldCode="MH" term="%22Inflammation+immunology%22">immunology</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22cGAS-STING+Signaling+Pathway%22">cGAS-STING Signaling Pathway</searchLink> ; <searchLink fieldCode="MH" term="%22STING+Protein%22">STING Protein</searchLink> ; <searchLink fieldCode="MH" term="%22Cyclic+Guanosine+Monophosphate-Adenosine+Monophosphate+Synthase%22">Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Homeostasis%22">Homeostasis</searchLink> ; <searchLink fieldCode="MH" term="%22Signal+Transduction%22">Signal Transduction</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: In addition to cell cycle arrest, cellular senescence is characterized by disrupted mitochondrial homeostasis, development of the senescence-associated secretory phenotype (SASP), and alterations in the immune microenvironment. Mitochondrial membrane damage, disrupted mitochondrial dynamics, and impaired mitochondrial quality control (MQC) can occur during cellular senescence. These changes may cause mitochondrial DNA (mtDNA) to leak abnormally into the cytosol. Cytosolic mtDNA can then activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Unlike the acute innate immune response elicited by pathogen-derived DNA, cGAS-STING signaling in senescent cells is mainly activated by the aberrant cytosolic accumulation of endogenous DNA. This signaling activates the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) axis and induces a type I interferon response. It also promotes nuclear factor kappaB (NF-κB)-mediated inflammatory transcription, sustains the SASP, and modulates paracrine signaling and immune cell function. This review focuses on mitochondrial structural damage, mtDNA release, and impaired MQC. It summarizes the mechanisms that activate the mtDNA-cGAS-STING axis during cellular senescence and examines its functional changes. It also discusses the potential development of senescence-associated biomarkers. Current evidence suggests that this signaling axis mainly contributes to the maintenance and amplification of the inflammatory senescence phenotype. It is unlikely to independently determine the onset of cellular senescence. Its effects are highly dependent on cell type and pathological context, while assay standards, causal relationships, and therapeutic windows require further clarification.<br /> (© 2026. The Author(s), under exclusive licence to Springer Nature B.V.) – Name: Abstract Label: Competing Interests Group: Ab Data: Declarations. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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(PMID: <searchLink fieldCode="PM" term="%2210%2E1038%2Fs41467-023-43889-63808184710713658%22">10.1038/s41467-023-43889-63808184710713658)</searchLink> – Name: GrantInfo Label: Grant Information Group: Grant Data: 81403232 National Natural Science Foundation of China; 19KJA480003 Major Programs of Natural Science Foundation of higher education in Jiangsu Province; BK20171290 Natural Science Foundation of Jiangsu Province; BY20240547 Industry-University-Research Collaboration Project of Jiangsu Province – Name: SubjectMinor Label: Contributed Indexing Group: Data: <i>Keywords: </i>CGAS-STING; Cellular senescence; Immunomodulation; Inflammatory senescence; Mitochondrial DNA; SASP – Name: NumberCAS Label: Substance Nomenclature Group: ID Data: 0 (DNA, Mitochondrial)<br />0 (STING Protein)<br />EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase)<br />0 (Membrane Proteins)<br />0 (STING1 protein, human)<br />EC 2.7.7.- (Nucleotidyltransferases)<br />EC 2.7.7.- (cGAS protein, human) – Name: DateEntry Label: Entry Date(s) Group: Date Data: <i>Date Created: </i>20261003 <i>Date Completed: </i>20261003 <i>Latest Revision: </i>20261003 – Name: DateUpdate Label: Update Code Group: Date Data: 20261004 – Name: DOI Label: DOI Group: ID Data: 10.1007/s10522-026-10515-z – Name: AN Label: PMID Group: ID Data: 42828712
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RecordInfo	BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1007/s10522-026-10515-z Languages: – Code: eng Text: English Subjects: – SubjectFull: Inflammation immunology Type: general – SubjectFull: Humans Type: general – SubjectFull: cGAS-STING Signaling Pathway Type: general – SubjectFull: STING Protein Type: general – SubjectFull: Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Type: general – SubjectFull: Animals Type: general – SubjectFull: Homeostasis Type: general – SubjectFull: Signal Transduction Type: general – SubjectFull: DNA, Mitochondrial metabolism Type: general – SubjectFull: DNA, Mitochondrial genetics Type: general – SubjectFull: Cellular Senescence immunology Type: general – SubjectFull: Cellular Senescence physiology Type: general – SubjectFull: Mitochondria metabolism Type: general – SubjectFull: Mitochondria immunology Type: general – SubjectFull: Membrane Proteins metabolism Type: general – SubjectFull: Nucleotidyltransferases metabolism Type: general Titles: – TitleFull: Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Zhang Y – PersonEntity: Name: NameFull: Zhu J – PersonEntity: Name: NameFull: Cui L – PersonEntity: Name: NameFull: Chen S – PersonEntity: Name: NameFull: Li X – PersonEntity: Name: NameFull: Gao L – PersonEntity: Name: NameFull: Chen X – PersonEntity: Name: NameFull: Wen K – PersonEntity: Name: NameFull: Zeng B – PersonEntity: Name: NameFull: Qian Y IsPartOfRelationships: – BibEntity: Dates: – D: 03 M: 10 Text: 2026 Oct 03 Type: published Y: 2026 Identifiers: – Type: issn-electronic Value: 1573-6768 Numbering: – Type: volume Value: 27 – Type: issue Value: 5 Titles: – TitleFull: Biogerontology Type: main
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