Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.

Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPRmt) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPRmt-MM) and IMS (UPRmt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPRmt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPRmt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPRmt signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.