Subcellular NAMPT‐mediated NAD⁺ salvage pathways and their roles in bioenergetics and neuronal protection after ischemic injury

Sep 26, 2019Journal of neurochemistry

Cellular NAD+ recycling pathways and their roles in energy production and nerve cell protection after stroke-like injury

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Abstract

Neuronal mitochondria possess an intact machinery for the NAD salvage pathway, with NAMPT and NMNAT3 localized in the mitochondrial matrix.

Knocking down NMNAT1-3 and NAMPT shows that NMNAT3 significantly influences mitochondrial respiration linked to ATP production in primary cultured neurons.
NMNAT1-2 primarily affect glycolytic flux, demonstrating distinct roles for NMNAT isoforms in energy metabolism.
Over-expressing NAMPT in various cellular compartments equally protects neurons from damage during oxygen glucose deprivation.
The study highlights the importance of subcellular NAD salvage pathways in maintaining NAD levels and supporting neuronal survival under ischemic stress.

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NADis a cofactor required for glycolysis, tricarboxylic acid cycle, and complex I enzymatic reaction. In mammalian cells, NADis predominantly synthesized through the salvage pathway, where nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme. Previously, we demonstrated that NAMPT exerts a neuroprotective effect in ischemia through the suppression of mitochondrial dysfunction. Mammalian cells maintain distinct NADpools in the cytosol, mitochondria, and nuclei. However, it is unknown whether mitochondria have an intact machinery for NADsalvage, and if so, whether it plays a dominant role in bioenergetics, mitochondrial function, and neuronal protection after ischemia. Here, using mouse primary cortical neuron and cortical tissue preparations, and multiple technologies including cytosolic and mitochondrial subfractionation, viral over-expression of transgenes, molecular biology, and confocal microscopy, we provided compelling evidence that neuronal mitochondria possess an intact machinery of NAMPT-mediated NADsalvage pathway, and that NAMPT and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) are localized in the mitochondrial matrix. By knocking down NMNAT1-3 and NAMPT with siRNA, we found that NMNAT3 has a larger effect on basal and ATP production-related mitochondrial respiration than NMNAT1-2 in primary cultured neurons, while NMNAT1-2 have a larger effect on glycolytic flux than NMNAT3. Using an oxygen glucose deprivation model, we found that mitochondrial, cytoplasmic, and non-subcellular compartmental over-expressions of NAMPT have a comparable effect on neuronal protection and suppression of apoptosis-inducing factor translocation. The current study provides novel insights into the roles of subcellular compartmental NADsalvage pathways in NADhomeostasis, bioenergetics, and neuronal protection in ischemic conditions. + + + + + + +

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Subcellular NAMPT‐mediated NAD⁺ salvage pathways and their roles in bioenergetics and neuronal protection after ischemic injury

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