Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

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.

Pharmacokinetics and Therapeutic Potential of Teucrium polium, a Medicinal and Endangered Species in Ha'il Region, against Liver Damage Associated Hepatotoxicity and Oxidative Injury in Rats: Computational, Biochemical and Histological Studies

“…The molecular interactions of T. polium ’s major compounds with these key receptors, which are targeted in liver therapy, were studied. Both CYP and STING are considered key areas of focus for liver diseases, and thus constituted excellent targets for liver medication [ 36 , 37 ].…”

MLKL Deficiency Attenuated Hepatocyte Oxidative DNA Damage by Activating Mitophagy to Suppress Macrophage cGAS-STING Signaling During Liver Ischemia and Reperfusion Injury.

“…We previously showed that impaired mitophagy increases ROS-mediated hepatocyte pyroptosis to promote the extracellular release of mtDNA during acute liver injury (23). We also found that defective mitophagy ux in aged macrophages aggravates liver IR injury by promoting cytosolic mtDNA release and STING-NLRP3 activation (12). Failure to clear defective mitochondria via mitophagy drives autoimmune responses through mtDNA-dependent cGAS-STING activation (43).…”

“…(8-10) We previously found that mitochondrial DNA (mtDNA) from ischemia-stressed hepatocytes activates macrophage cGAS-STING signaling to promote nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3)-mediated in ammatory IR injury in aged livers. (11,12) The role of MLKL in regulating liver IR injury has recently been reported. (13) Inhibition of MLKL suppresses ischemia-induced hepatocyte necroptosis in vitro.…”

“…Recent studies have shown that the cGAS-STING pathway plays an important role in various liver diseases. (8, 9) We previously showed that liver IR triggers macrophage STING activation,(11) and STING inhibition attenuates different types of sterile in ammatory liver injuries, including liver IR (12). Moreover, mtDNA released from pyroptotic hepatocytes promotes macrophage cGAS-STING activation during acute liver injury.…”

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components

“…Specifically, the double-stranded DNA (ds DNA) sensor cyclic-GMP-AMP synthase (cGAS) and the downstream stimulator of interferon genes (STING) pathways (cGAS/STING) is emerging as an important regulator and therapeutic target of sterile inflammation and its unwarranted effects (Decout et al 2021 ; Huang et al 2020 ). Cytosolic dsDNA is recognized as a universal DAMP that acts as a ligand to activate cGAS/STING pathway, and the stress-induced cytosolic leakage of mitochondrial DNA (mt DNA), including in immune cells such as macrophages, has been implicated in augmented inflamm-aging that contributes to immunosenescence (Atayik and Çakatay 2022b ; Conte et al 2020 ; Lv et al 2022 ; Zhong et al 2022 ). Accumulating evidence suggests that inflamm-aging is essentially an age-dependent remodeling of the immune response due to an imbalance between anti-inflammatory and pro-inflammatory networks.…”