# The role of nicotinamide mononucleotide dependent mitochondrial reactive oxygen species generation in acute brain injury

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2021 · —

## Abstract

Impairments in mitochondrial functions have been frequently implicated in ischemic brain injury
associated with cardiac arrest or stroke. However, the extent to which mitochondrial dysfunction contributes
to neurodegeneration is unknown; and the mechanisms leading to mitochondrial failure are not well
understood. Recently, it was suggested that an imbalance in mitochondrial fission/fusion dynamics can lead
to neurodegeneration and brain damage. Furthermore, overactivation of nicotinamide adenine dinucleotide
(NAD)+ degrading poly-ADP-ribose polymerase (PARP1) causes excessive cellular and mitochondrial NAD+
depletion resulting in impaired cell survival. We hypothesize that the nicotinamide mononucleotide (NMN)
administration is inhibiting the post-ischemic neurodegeneration by (a) reversing excessive mitochondrial
fission via stimulation of mitochondrial NAD+ synthesis that (b) stimulates deacetylation of mitochondrial
proteins and leads to (c) reduction of mitochondrial superoxide production.
 Our preliminary data show that treatment of animals with NAD+ precursor NMN has dramatic
neuroprotection effect, reverses the excessive mitochondrial fragmentation and increases the brain
mitochondria NAD+ levels. As a downstream result NMN is decreasing mitochondrial proteins acetylation and
inhibits mitochondrial reactive oxygen species (ROS) production. The primary goal of this study is to
determine the mechanistic link(s) between NMN induced changes in mitochondrial NAD+ metabolism, protein
acetylation, ROS generation and inhibition of fission. To address these questions, we propose to:
 1. Determine the specific role of sirtuin 3 (SIRT3) in mitochondrial reactive oxygen species (ROS)
production, nucleotide metabolism, mitochondrial bioenergetic functions, and dynamics. Cells will be
prepared from our three transgenic animal models: (1) animals expressing mitochondria targeted enhanced
yellow fluorescence protein (mito-eYFP) alone, (2) animals expressing mito-eYFP and overexpressing SIRT3
(mito-eYFP-SIRT3OE), or (3) mito-eYFP expressing SIRT3 knockout animals (mito-eYFP-SIRT3KO). The
role of NMN-induced changes in mitochondrial protein acetylation on mitochondria ROS production,
mitochondrial fragmentation and cell death will be determined. Cellular NAD+ metabolism, mitochondrial
respiratory function, and mitochondrial fusion and fission will be analyzed and their role in NMN
neuroprotection and oxygen glucose deprivation induced cell death will be determined.
 2. To study the specific effect of NMN treatment on post-ischemic modulation of mitochondrial
dynamics in brain, we will use our transgenic animals that will be subjected to transient forebrain ischemia
and the post-ischemic alterations in neuronal mitochondrial morphometry will be examined. In addition, NMN-
induced changes in NAD+ metabolism, mitochondrial protein acetylation and mitochondrial ROS generation
will be determined. Additionally, NMN-induced changes in NAD+ metabolism, mitochondria...

## Key facts

- **NIH application ID:** 10106463
- **Project number:** 5I01BX004895-02
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** TIBOR KRISTIAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106463

## Citation

> US National Institutes of Health, RePORTER application 10106463, The role of nicotinamide mononucleotide dependent mitochondrial reactive oxygen species generation in acute brain injury (5I01BX004895-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10106463. Licensed CC0.

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