Mitochondrial NAD+ import gates neuronal resilience to active SARM1

Barbar, L.; Bhat, A.; Chen, S. J.; Strickland, A.; Schurr, S.; Sundali, S.; Kim, H.; Sasaki, Y.; Bloom, A. J.; Milbrandt, J.; DiAntonio, A.

doi:10.64898/2026.10.05.756890

bioRxiv · 10.64898/2026.10.05.756890

Mitochondrial NAD+ import gates neuronal resilience to active SARM1

Barbar, L.·Bhat, A.·Chen, S. J.·Strickland, A.·Schurr, S.·Sundali, S.·Kim, H.·Sasaki, Y.·Bloom, A. J.·Milbrandt, J.·DiAntonio, A.

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Abstract

SARM1 is an inducible NADase that executes pathological axon degeneration, but how NAD+ destruction causes neuronal failure remains unclear. Because SARM1 is predicted to act outside the mitochondrial matrix, cytosolic NAD+ loss has been viewed as the critical lethal lesion. We show that SARM1 activation rapidly depletes cytosolic and mitochondrial NAD+ and collapses ATP in both compartments, revealing early, coupled metabolic failure. Enhancing mitochondrial NAD+ import through SLC25A51, the mitochondrial NAD+ transporter, preserves mitochondrial NAD+, maintains mitochondrial function, and delays axon degeneration and neuronal death despite ongoing SARM1 activity. Unexpectedly, SLC25A51 restores cytosolic NAD+-dependent metabolism, reversing a glycolytic block and increasing NAD+ synthesis during stress. Glycolytic inhibition attenuates protection, identifying cytosolic metabolic recovery as an important component of neuronal resilience. AAV-SLC25A51 improves function in a chronic SARM1-dependent neuropathy model. Thus, mitochondrial NAD+ import gates SARM1-driven degeneration by limiting coupled mitochondrial-cytosolic metabolic failure, presenting a downstream intervention point for axon preservation.

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Barbar, L., Bhat, A., Chen, S. J., Strickland, A., Schurr, S., Sundali, S., Kim, H., Sasaki, Y., Bloom, A. J., Milbrandt, J., DiAntonio, A.. 2026-10-11. Mitochondrial NAD+ import gates neuronal resilience to active SARM1. https://doi.org/10.64898/2026.10.05.756890

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