Mitophagy and cGAS–STING crosstalk in neuroinflammation

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS–STING pathway. We critically evaluated the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, activating the cGAS–STING pathway. This activation prompts the production of proinflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS–STING pathway. Effective mitophagy might suppress the cGAS–STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS–STING pathway, potentially leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy–cGAS–STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, which could lead to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues in neurodegenerative disease research.