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bioRxiv · 10.1101/2025.06.07.658365

Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment

D'Alessandro, K. B.·Zampese, E.·Blum, J. L. E.·Kuusik, B.·Palmiotti, A.·Davidson, S. M.·Reczek, C. R.·Surmeier, D. J.·Chandel, N. S.
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Abstract

Dysfunction of mitochondrial complex I (MCI) has been implicated in the degeneration of dopaminergic neurons in Parkinsons disease. Here, we report the effect of expressing MitoLbNOX, a mitochondrial-targeted version of the bacterial enzyme LbNOX, which increases regeneration of NAD+ in the mitochondria to maintain the NAD+/NADH ratio, in dopaminergic neurons with impaired MCI (MCI-Park mice). MitoLbNOX expression did not ameliorate the cellular or behavioral deficits observed in MCI-Park mice, suggesting that alteration of the mitochondrial NAD+/NADH ratio alone is not sufficient to compensate for loss of MCI function in dopaminergic neurons.

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D'Alessandro, K. B., Zampese, E., Blum, J. L. E., Kuusik, B., Palmiotti, A., Davidson, S. M., Reczek, C. R., Surmeier, D. J., Chandel, N. S.. 2025-06-08. Genetic modulation of mitochondrial NAD+ regeneration does not prevent dopaminergic neuron dysfunction caused by mitochondrial complex I impairment. https://doi.org/10.1101/2025.06.07.658365

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