Abstract / Summary
Brain aging is characterized by heterogeneous microglial states and altered mitochondrial, metabolic, and lysosomal homeostasis. Mitophagy is central to mitochondrial quality control, but its contribution to age-associated microglial dysfunction remains incompletely understood. This review examines how microglial mitophagy interacts with mitochondrial and lysosomal quality control, immunometabolic adaptation, and inflammatory signaling during brain aging, while distinguishing direct microglial evidence from findings derived from other experimental systems. Aging remodels microglial mitochondrial, metabolic, and lysosomal functions in a state- and context-dependent manner, including reactive, disease-associated, lipid-associated, and senescence-like states. Mitophagy may preserve mitochondrial quality control by limiting the accumulation of damaged mitochondria and associated oxidative and danger signals. However, static mitophagy-associated markers do not establish completed mitophagic flux, which requires mitochondrial delivery to lysosomes and subsequent degradation within them. Human postmortem studies reveal age- and disease-associated alterations in mitochondrial quality control and mitophagy-related pathways, but direct measurements of mitophagic flux in defined human microglial populations remain limited. Age-related changes in lysosomal capacity, acidification, metabolic stress, mitochondrial dynamics, and coordination between mitochondrial clearance and biogenesis may collectively influence microglial resilience. Whether phagocytic and mitophagic cargo directly compete for lysosomal capacity remains unproven. We therefore propose a Microglial Mitophagy Threshold Model as a conceptual, testable framework in which mitochondrial damage, mitophagic clearance, lysosomal capacity, mitochondrial renewal, and microglial state collectively determine mitochondrial homeostasis or persistent inflammatory dysfunction. Microglial mitophagy should be viewed as part of an interconnected mitochondrial–lysosomal quality control network. Direct assessment of mitophagic flux alongside microglial state, mitochondrial dynamics and function, bioenergetics, and lysosomal capacity will be essential to validate this framework.