Restoring mitochondrial redox balance enhances ribosome-associated quality control to mitigate Alzheimer’s disease pathology

Mitochondrial dysfunction and proteostasis failure are early and concurrent features of Alzheimer’s disease and other neurodegenerative diseases, yet the mechanistic links between them remain unclear. Here we demonstrate that Drosophila models expressing Alzheimer’s disease-related amyloid precursor protein or its C-terminal C99 fragment in the muscle exhibit disruption of mitochondrial complex I assembly and activity, NAD⁺ depletion, mitochondrial stress, and impaired ribosome-associated quality control. Restoration of NAD⁺/NADH balance using yeast NDI1, which bypasses dysfunctional complex I, robustly rescues these cellular defects and ameliorates muscular and neuronal phenotypes in the AD models. Mechanistically, NDI1 activates a mitochondrial Sirtuin–VCP axis that prevents the formation of the amyloidogenic, aberrant ribosome-associated quality control products of amyloid precursor protein and promotes their clearance through ATG5-dependent but ATG1-independent autophagy. Disruption of NAD⁺ biosynthesis abolishes NDI1-mediated protection, highlighting the critical role of NAD⁺ availability. NDI1 also modulates the Sirtuin–VCP axis and is protective in human iPSC-derived neuronal AD models. Our findings validate the key pathogenic role of aberrant translational control of amyloid precursor protein in causing proteostasis failure and provide an unexpected mechanistic link between mitochondrial redox balance and proteostasis. These findings have important implications for the mechanistic understanding and therapeutic development for Alzheimer’s disease. Genetic studies in Drosophila demonstrate that yeast NDI1 rescues Alzheimer’s disease models by promoting a mitochondrial Sirtuin–VCP axis that prevents the formation of the amyloidogenic, aberrant ribosome-associated quality control products of the amyloid precursor protein.