A Therapeutic Approach to Falling NAD+ Levels After Brain Injury

Scientists elaborate how NAD+ depletion compromises the ability of mitochondria to counteract free radical and reactive oxygen species buildup.

· Scientific Research,Neurological,Metabolism
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By Brett J. Weiss

Published: 2:40 p.m. PST Jul 21, 2020 | Updated: 5:30 p.m. PST Oct 5, 2020

Following brain injury and during the progression of neurodegenerative diseases, the major power-generating components of the cell, the mitochondria, release reactive molecules known as free radicals that can cause further cellular damage. Recently, scientists from the University of Maryland published a review in Brain Sciences where they elaborated on a possible molecular mechanism whereby mitochondria counteract the buildup of free radicals following brain injury and identified a potential therapeutic approach.

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(Klimova et al., 2020 | Brain Sciences) Reduced NAD+ levels following brain injury inhibit the activity of the NAD+ dependent enzyme SIRT3. MnSOD acetylation accumulates without SIRT3 to remove acetylation (i.e., deacetylation). With inhibited MnSOD activity, the reactive oxygen species superoxide (O2) builds up causing mitochondrial pathology.

When NAD+ levels are reduced in situations like brain injury, enzymes with essential functional roles in reactive oxygen species detoxification like MnSOD are inhibited, leading to free radical and reactive oxygen species buildup. “Our published data show that the delayed increase in brain tissue ROS levels following an acute brain injury is due to inhibition of the mitochondrial antioxidant mechanisms triggered by mitochondrial NAD+ catabolism and consequent hyperacetylation of enzymes, whose activities are essential for superoxide detoxification,” stated the investigators in the paper.

Researchers have used a molecule to boost NAD+ levels called nicotinamide mononucleotide (NMN) to counteract the age-related decline in reduced cellular NAD+ levels with age. The authors of this review suggest that NMN supplementation may constitute a therapeutic approach to mitigate the effects of reduced NAD+ levels from brain injury by preventing the depletion of NAD+ levels in mitochondria. Since increased concentrations of reactive oxygen species in mitochondria are damaging to cells, using NMN may improve clinical outcomes following reduced blood flow to the brain from injury. 


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Klimova N, Fearnow A, Kristian T. Role of NAD+-Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury. Brain Sci. 2020 Jul 14;10(7):449. doi: 10.3390/brainsci10070449. PMID: 32674501; PMCID: PMC7408119.

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