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Mitophagy mitigates mitochondrial dysfunction-triggered activation of mtDNA-cGAS-STING inflammation during autoimmune thyroiditis

ABSTRACT: Autoimmune thyroiditis (AIT) is a common endocrine disorder characterized by the destruction of thyroid follicles and lymphocytic infiltration, yet its pathogenic mechanisms are not fully understood. This study reveals that chronic oxidative stress during thyroid hormone synthesis in follicular epithelial cells leads to mitochondrial damage and dysfunction. A key finding is the cytosolic leakage of mitochondrial DNA (mtDNA) resulting from this damage, which activates the cGAS-STING innate immune signaling pathway, driving the production of proinflammatory cytokines and exacerbating disease pathogenesis. Conversely, we identify a protective, adaptive mitophagy pathway mediated by the ATM-CHK2 axis. Upon mitochondrial stress, activated CHK2 translocates to mitochondria and phosphorylates the selective autophagy adapter TAX1BP1 at Ser722. This phosphorylation event enhances TAX1BP1's affinity for K63-linked ubiquitin chains on damaged mitochondria, facilitating their clearance via PINK1/Parkin-dependent mitophagy. Impairment of this ATM-CHK2-TAX1BP1 pathway, or genetic ablation of PINK1/Parkin, abrogates mitophagy, leading to amplified mtDNA leakage and hyperactivation of cGAS-STING signaling. Crucially, pharmacological inhibition of STING with C-176 significantly attenuates thyroiditis progression in mouse models.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Qiqiang Guo

PROVIDER: PXD070578 | iProX | Tue Nov 11 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

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Mitophagy mitigates mitochondrial dysfunction-triggered activation of mtDNA-cGAS-STING inflammation during autoimmune thyroiditis

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