ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia

Apr 8, 2026Acta pharmacologica Sinica

ADT-OH helps clear damaged mitochondria and reduces inflammation signaling in brain immune cells

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Abstract

ADT-OH induces mitophagic flux in microglia, reducing levels of mitochondrial marker proteins.

Mitochondrial dysfunction is linked to neurodegenerative disorders like Parkinson's disease.
Mitophagy selectively removes dysfunctional mitochondria, which is crucial for cellular health.
ADT-OH promotes mitophagy through mechanisms involving mitochondrial uncoupling and activation of specific signaling pathways.
In microglia exposed to α-synuclein preformed fibrils, ADT-OH prevents the accumulation of dysfunctional mitochondria and mitigates inflammatory responses.
Systemic ADT-OH administration reduced microglial activation and improved motor coordination in α-Syn-overexpressing Parkinson's disease mice.

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Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release HS compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of HS. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation. 2 2

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ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia

Abstract

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