ArticleAging cell2022
Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers, 1 of them a synthesis that pooled it.
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Who cites it
120 citing papers in PubMed, 1 synthesis or guideline pooled it, 158 citations in OpenAlex.
- Molecular mechanisms and therapeutic strategies of cGAS-STING pathway in liver disease: the quest continues.Frontiers in immunology · 2025Pooled it
- Mitochondrial mechanisms underlying spatial immune phenotypes in non‑small cell lung cancer: Implications for ICI response and cold‑to‑hot tumor conversion (Review).Oncology reports · 2026Review
- Nucleic acid sensing pathways in kidney disease development.Nature reviews. Nephrology · 2026Review
- Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.Biogerontology · 2026Review
- From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).Experimental and therapeutic medicine · 2026Review
- Mitochondrial Transplantation Suppresses mtDNA-cGAS/STING-Mediated Innate Immunity by Enhancing PINK1/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis.Antioxidants (Basel, Switzerland) · 2026Article
- Tissue-Resident Macrophage in Inflammation and Cancer.MedComm · 2026Review
- PINK1-Parkin pathway-mediated mitophagy in sepsis: friend or foe?Molecular biology reports · 2026Review
- KLF5 Downregulation Links Impaired BNIP3-Mediated Mitophagy to Inflammatory Valve Remodeling in Calcific Aortic Valve Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- STING deficiency does not rescue short telomere-mediated aging phenotypes and longevity in TERC- or TERT-telomerase deficient mice.Cell reports · 2026Article
- cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.Archives of pharmacal research · 2026Review
- Review
- From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- TIA-1 promotes FUNDC1-mediated mitophagy to protect against stress-induced cellular senescence.Experimental & molecular medicine · 2026Article
- Senescent BMSC-Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing PINK1/Parkin-Mediated Mitophagy in Macrophages.Aging cell · 2026Article
- Mitochondrial drivers of stem cell aging and inflammaging.npj aging · 2026Review
- Integrated transcriptomic analysis identifies liver aging-driven fibrosis signatures and reveals therapeutic strategies based on medicine-food homology.NPJ science of food · 2026Article
- Review
- Hematopoietic Aging and Leukemia: Mechanistic and Therapeutic Insights.International journal of molecular sciences · 2026Review
60 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.