UQCRC1 is a Key Pathogenic Determinant and Potential Therapeutic Target for Cognitive Impairment in Alzheimer's...

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia, yet it remains incurable. Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), a pivotal subunit of mitochondrial complex III, has been implicated in Alzheimer's disease pathogenesis, though its precise mechanistic contributions remain undefined. In this study, we systematically investigated the mechanistic involvement of UQCRC1 in AD pathogenesis. Our findings reveal significant downregulation of UQCRC1 expression in hippocampal tissues from both AD patients and APP/PS1 transgenic mice. Conditional UQCRC1 knockdown in AD model mice exacerbated cognitive deficits while transmission electron microscopy analysis demonstrated that UQCRC1 deficiency induces pathological lysosomal enlargement, lipofuscin accumulation, and increased neuronal apoptosis in hippocampal neurons. Mechanistic interrogation revealed that UQCRC1 depletion triggers lysosomal Ca²⁺ overload-mediated proteolytic dysfunction coupled with activation of neuronal apoptotic pathways. Notably, adeno-associated virus-mediated UQCRC1 overexpression effectively reversed these pathological manifestations. Molecular dissection identified AMP-activated protein kinase (AMPK) signaling as the critical mechanistic mediator of this rescue effect, as pharmacological AMPK inhibition completely abrogated the therapeutic benefits. Together, our findings delineate a novel pathogenic axis linking mitochondrial complex III dysfunction to lysosomal degradation failure through UQCRC1-mediated AMPK regulation. These results position UQCRC1 not only as a promising biomarker for AD progression but also as a mechanistically validated therapeutic target, offering new insights into mitochondrial-lysosomal crosstalk in Alzheimer's disease pathology.