A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19
Medina, T.; Quinones, S.; Liu, Z.; Wu, L.; Ziani, B.; Shedlock, C.; Ma, X.; Ryan, A.; Larson, R.; Soto, C. M.; Barco-Caiaffa, V.; Titus, A.; Wong, K.; Rao, N.; Florea, S.; Gutierrez-Monreal, M. A.; Mitchell, G. S.; Vander Kooi, C. W.; Gentry, M. S.; Chandel, N. S.; Esser, K. A.; Sun, R. C.
Show abstract
We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.
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