NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses

Narayan Dey, P.; Bueno, D.; Schacht, T.; Wolf, C.; Wüllner, V.; Morpurgo, E.; Rojas-Charry, L.; Sessinghaus, L.; Leukel, P.; Sommer, C.; Radyushkin, K.; Schaefer, M.; Florin, L.; Tenzer, S.; Baumgart, J.; Stamm, P.; Daiber, A.; Horta, G.; Nardi, L.; Vasic, V.; Schmeisser, M. J.; Hellwig, A.; Oskamp, A.; Bauer, A.; Anand, R.; Reichert, A. S.; Ritz, S.; Silies, M.; Frauenknecht, K. B. M.; Methner, A.

doi:10.1101/2021.02.15.431234

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bioRxiv · 10.1101/2021.02.15.431234

NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses

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Abstract

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control and repair. We found that global knockout of the neuronal calcium-binding protein 2 (NECAB2) in the mouse causes loss of striatal synapses and behavioral phenotypes related to striatal dysfunction such as reduced motivation and altered sensory gating. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller. They are characterized by increased respiration and superoxide production resulting in oxidative stress. This accumulation of dysfunctional mitochondria is caused by a defective assembly of mitochondria with early endosomes in a pathway that involves the small GTPase Rab5 and its guanine nucleotide exchange factor Alsin/ALS2. NECAB2 therefore participates in an endosomal pathway of mitochondrial stress response and repair important for striatal function.

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Narayan Dey, P., Bueno, D., Schacht, T., Wolf, C., Wüllner, V., Morpurgo, E., Rojas-Charry, L., Sessinghaus, L., Leukel, P., Sommer, C., Radyushkin, K., Schaefer, M., Florin, L., Tenzer, S., Baumgart, J., Stamm, P., Daiber, A., Horta, G., Nardi, L., Vasic, V., Schmeisser, M. J., Hellwig, A., Oskamp, A., Bauer, A., Anand, R., Reichert, A. S., Ritz, S., Silies, M., Frauenknecht, K. B. M., Methner, A.. 2021-02-17. NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses. https://doi.org/10.1101/2021.02.15.431234

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