Microglial mitophagy as an immunometabolic checkpoint in alzheimer’s disease: linking mitochondrial quality control to neuroinflammation

Abstract

AD is a complex neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the brain’s resident immune cells, centrally regulate AD pathophysiology. Recent studies have highlighted microglial mitophagy as an important interface linking mitochondrial quality control to innate immune responses.Intact mitophagy facilitates the timely clearance of damaged mitochondria, thereby limiting the release of mitochondrial DAMPs (e.g., mtDNA and mtROS) and helping restrain aberrant activation of the cGAS-STING pathway and the NLRP3 inflammasome.In the AD pathological milieu, however, factors including Aβ deposition, tau pathology, and genetic risk variants such as TREM2 and APOE4 disrupt mitophagy at multiple levels—from initiation and recognition to lysosomal degradation. This review systematically summarizes the molecular regulatory network of microglial mitophagy, with a particular focus on the mechanisms by which AD-associated pathological factors impair this process. We further discuss potential mechanisms through which mitophagic dysfunction may contribute to the amplification of neuroinflammation, including the release of mitochondrial DAMPs, the reprogramming of TBK1 signaling, and intercellular interactions. Finally, we outline current therapeutic strategies aimed at restoring mitophagy and discuss their potential to modulate neuroinflammatory responses and AD-related pathological processes, while highlighting the challenges and future directions in this emerging field.