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Ischemic Neuroprotectant PKCε Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury

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Abstract

The preservation of mitochondrial function is a major protective strategy for cerebral ischemic injuries. Previously, our laboratory demonstrated that protein kinase C epsilon (PKCε) promotes the synthesis of mitochondrial nicotinamide adenine dinucleotide (NAD+). NAD+ along with its reducing equivalent, NADH, is an essential co-factor needed for energy production from glycolysis and oxidative phosphorylation. Yet, NAD+/NADH are impermeable to the inner mitochondrial membrane and their import into the mitochondria requires the activity of specific shuttles. The most important neuronal NAD+/NADH shuttle is the malate-aspartate shuttle (MAS). The MAS has been implicated in synaptic function and is potentially dysregulated during cerebral ischemia. The aim of this study was to determine if metabolic changes induced by PKCε preconditioning involved regulation of the MAS. Using primary neuronal cultures, we observed that the activation of PKCε enhanced mitochondrial respiration and glycolysis in vitro. Conversely, inhibition of the MAS resulted in decreased oxidative phosphorylation and glycolytic capacity. We further demonstrated that activation of PKCε increased the phosphorylation of key components of the MAS in rat brain synaptosomal fractions. Additionally, PKCε increased the enzyme activity of glutamic oxaloacetic transaminase 2 (GOT2), an effect that was dependent on the import of PKCε into the mitochondria and phosphorylation of GOT2. Furthermore, PKCε activation was able to rescue decreased GOT2 activity induced by ischemia. These findings reveal novel protective targets and mechanisms against ischemic injury, which involves PKCε-mediated phosphorylation and activation of GOT2 in the MAS.

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Acknowledgements

We would like to thank Clemer Abad for his assistance with the real-time PCR experiments.

Funding

This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants NS45676, NS097658, and NS34773 (to M.A.P.P.), and the American Heart Association (AHA) predoctoral award 19PRE34400074 (to J.X.).

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Authors and Affiliations

  1. Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, Miami, FL, 33136, USA

    Jing Xu, Nathalie Khoury, Charles W. Jackson, Iris Escobar, Samuel D. Stegelmann, Kunjan R. Dave & Miguel A. Perez-Pinzon

  2. Department of Neurology, University of Miami Leonard M. Miller School of Medicine, P.O. Box 016960, Miami, FL, 33136, USA

    Jing Xu, Nathalie Khoury, Charles W. Jackson, Iris Escobar, Samuel D. Stegelmann, Kunjan R. Dave & Miguel A. Perez-Pinzon

  3. Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, Miami, FL, 33136, USA

    Jing Xu, Nathalie Khoury, Charles W. Jackson, Iris Escobar, Kunjan R. Dave & Miguel A. Perez-Pinzon

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Correspondence to Miguel A. Perez-Pinzon.

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Xu, J., Khoury, N., Jackson, C.W. et al. Ischemic Neuroprotectant PKCε Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury. Transl. Stroke Res. 11, 418–432 (2020). https://doi.org/10.1007/s12975-019-00729-4

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