Mitochondrial NAD⁺ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial...

Cerebral ischemia-reperfusion (I/R) injury is a leading cause of neurological disability and is characterized by mitochondrial dysfunction and oxidative stress. Although depletion of nicotinamide adenine dinucleotide (NAD⁺) is a hallmark of ischemic injury, therapeutic strategies aimed at NAD⁺ replenishment have shown limited efficacy. Whether impaired mitochondrial NAD⁺ import contributes to neuronal vulnerability after I/R remains poorly understood.

We found that cerebral I/R disrupts the balance of NAD⁺ distribution between the cytoplasm and mitochondria in the cortex due to upregulated expression of SLC25A51. Augmenting SLC25A51 expression restored mitochondrial NAD⁺ pools, improved mitochondrial respiratory function, reduced oxidative lipid damage, and attenuated neuronal injury. In contrast, SLC25A51 deficiency exacerbated mitochondrial dysfunction and heightened susceptibility to I/R stress. These effects occurred independently of global NAD⁺ biosynthesis, indicating that mitochondrial NAD⁺ transport rather than NAD⁺ availability per se is a critical determinant of neuronal survival.

This study reveals the subcellular distribution change of NAD⁺-mediated by SLC25A51 and its neuroprotective effects via modulating mitochondrial function after cerebral I/R injury.

This study identifies defective mitochondrial NAD⁺ import as a previously underrecognized mechanism of cerebral I/R injury. By establishing SLC25A51-dependent NAD⁺ trafficking as a key regulator of mitochondrial redox balance and neuronal resilience, our findings shift the therapeutic paradigm from NAD⁺ supplementation to restoration of subcellular NAD⁺ distribution, highlighting mitochondrial NAD⁺ transport as a promising target for ischemic brain injury. Antioxid. Redox Signal. 45, 359-375.