Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer's Disease-Related Models

Mitochondria are key organelles for brain health. Mito-chondrial alterations have been reported in severalneurodegenerative disorders, including Alzheimer'sdisease (AD), and the comprehension of the underly-ing mechanisms appears crucial to understand theirrelationship with the pathology. Using multiplegenetic, pharmacological, imaging, and biochemicalapproaches, we demonstrate that, in different familialAD cell models, mitochondrial ATP synthesis isaffected. The defect depends on reduced mitochon-drial pyruvate oxidation, due to both lower Ca2+-medi-ated stimulation of the Krebs cycle and dampenedmitochondrial pyruvate uptake. Importantly, this latterevent is linked to glycogen-synthase-kinase-3b(GSK-3b) hyper-activation, leading, in turn, toimpaired recruitment of hexokinase 1 (HK1) tomitochondria, destabilization of mitochondrial-pyru-vate-carrier (MPC) complexes, and decreased MPC2protein levels. Remarkably, pharmacological GSK-3binhibition in AD cells rescues MPC2 expression andimproves mitochondrial ATP synthesis and respira-tion. The defective mitochondrial bioenergeticsinfluences glutamate-induced neuronalexcitotoxicity,thus representing a possible target for futuretherapeutic interventions