Microglial Vulnerability to Mitochondrial Proteotoxic Stress: A Failed-Resolution Framework for Neurodegeneration

Microglial responses to mitochondrial protein stress are best evaluated by connecting the initiating protein burden to its processing and functional consequences. This review develops an outcome-based failed-resolution framework that integrates burden trajectory, clearance or repair, and lesion-relevant functional recovery. Stress-response activation is evaluated separately from successful proteostasis restoration. Failed resolution requires persistent initiating burden AND insufficient corresponding processing AND inadequate functional recovery after a defined withdrawal or rescue interval; these are measurement domains, not obligatory biological stages. Matched human induced pluripotent stem cell-derived neural cultures show preferential microglial aggregate-associated signals and multidomain senescence-associated changes under common exposure, while vulnerability at an equivalent intracellular burden remains to be tested. Substrate-resolved turnover and functional measurements anchor the interpretation of stress markers, bulk autophagy and extracellular-cargo uptake. Proteostasis status, functional adequacy and cell fate are assessed independently, allowing a persistent phenotype after burden clearance to be distinguished from ongoing unresolved stress. Resource competition between mitochondrial maintenance and phagolysosomal work is a testable hypothesis supported by component findings. Human cellular, organoid and animal studies define these components; their complete integration in adult microglia in vivo remains untested. The framework provides falsifiable comparisons and selective-rescue tests for linking protein handling to cell-specific recovery.