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 (UPR^mt) 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 (UPR^mt-MM) and IMS (UPR^mt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPR^mt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPR^mt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPR^mt 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.