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.

doi:10.64898/2026.06.16.732673

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bioRxiv · 10.64898/2026.06.16.732673

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

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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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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.. 2026-06-22. 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. https://doi.org/10.64898/2026.06.16.732673

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