Abstract:
:Global cerebral ischemia depletes brain tissue NAD+, an essential cofactor for mitochondrial and cellular metabolism, leading to bioenergetics failure and cell death. The post-ischemic NAD+ levels can be replenished by the administration of nicotinamide mononucleotide (NMN), which serves as a precursor for NAD+ synthesis. We have shown that NMN administration shows dramatic protection against ischemic brain damage and inhibits post-ischemic hippocampal mitochondrial fragmentation. To understand the mechanism of NMN-induced modulation of mitochondrial dynamics and neuroprotection we used our transgenic mouse models that express mitochondria targeted yellow fluorescent protein in neurons (mito-eYFP) and mice that carry knockout of mitochondrial NAD+-dependent deacetylase sirt3 gene (SIRT3KO). Following ischemic insult, the mitochondrial NAD+ levels were depleted leading to an increase in mitochondrial protein acetylation, high reactive oxygen species (ROS) production, and excessive mitochondrial fragmentation. Administration of a single dose of NMN normalized hippocampal mitochondria NAD+ pools, protein acetylation, and ROS levels. These changes were dependent on SIRT3 activity, which was confirmed using SIRT3KO mice. Ischemia induced increase in acetylation of the key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) that resulted in inhibition of its activity. This was reversed after NMN treatment followed by reduction of ROS generation and suppression of mitochondrial fragmentation. Specifically, we found that the interaction of mitochondrial fission protein, pDrp1(S616), with neuronal mitochondria was inhibited in NMN treated ischemic mice. Our data thus provide a novel link between mitochondrial NAD+ metabolism, ROS production, and mitochondrial fragmentation. Using NMN to target these mechanisms could represent a new therapeutic approach for treatment of acute brain injury and neurodegenerative diseases.
journal_name
Exp Neuroljournal_title
Experimental neurologyauthors
Klimova N,Fearnow A,Long A,Kristian Tdoi
10.1016/j.expneurol.2019.113144subject
Has Abstractpub_date
2020-03-01 00:00:00pages
113144eissn
0014-4886issn
1090-2430pii
S0014-4886(19)30291-2journal_volume
325pub_type
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