Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock
Carrie A. Sims, Yuxia Guan, Sarmistha Mukherjee, Khushboo Singh, Paul Botolin, Antonio Davila Jr., Joseph A. Baur
Carrie A. Sims, Yuxia Guan, Sarmistha Mukherjee, Khushboo Singh, Paul Botolin, Antonio Davila Jr., Joseph A. Baur
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Research Article Inflammation Metabolism

Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock

Abstract

Hemorrhagic shock depletes nicotinamide adenine dinucleotide (NAD) and causes metabolic derangements that, in severe cases, cannot be overcome, even after restoration of blood volume and pressure. However, current strategies to treat acute blood loss do not target cellular metabolism. We hypothesized that supplemental nicotinamide mononucleotide (NMN), the immediate biosynthetic precursor to NAD, would support cellular energetics and enhance physiologic resilience to hemorrhagic shock. In a rodent model of decompensated hemorrhagic shock, rats receiving NMN displayed significantly reduced lactic acidosis and serum IL-6 levels, two strong predictors of mortality in human patients. In both livers and kidneys, NMN increased NAD levels and prevented mitochondrial dysfunction. Moreover, NMN preserved mitochondrial function in isolated hepatocytes cocultured with proinflammatory cytokines, indicating a cell-autonomous protective effect that is independent from the reduction in circulating IL-6. In kidneys, but not in livers, NMN was sufficient to prevent ATP loss following shock and resuscitation. Overall, NMN increased the time animals could sustain severe shock before requiring resuscitation by nearly 25% and significantly improved survival after resuscitation (P = 0.018), whether NMN was given as a pretreatment or only as an adjunct during resuscitation. Thus, we demonstrate that NMN substantially mitigates inflammation, improves cellular metabolism, and promotes survival following hemorrhagic shock.

Authors

Carrie A. Sims, Yuxia Guan, Sarmistha Mukherjee, Khushboo Singh, Paul Botolin, Antonio Davila Jr., Joseph A. Baur

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Figure 2

NMN increases NAD and NADH and preserves renal ATP following resuscitation from hemorrhagic shock.

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NMN increases NAD and NADH and preserves renal ATP following resuscitati...
NAD, NADH, and ATP levels were measured in extracts from snap frozen tissues harvested 1 hour after 90 minutes of hemorrhagic shock, followed by resuscitation with or without NMN (400 mg/kg). In the kidney, NMN increased the NAD and NADH levels in both sham (n = 5–6 per treatment group) and shocked animals (9–12 per treatment group) and prevented the sharp decline in the NAD/NADH ratio observed in shocked animals (A). In the liver, NMN increased NAD levels in both sham and shocked animals but only increased NADH significantly in shocked animals, while again preserving the NAD/NADH ratio (B). ATP levels declined in both tissues following hemorrhagic shock and resuscitation (C and D). Treatment with NMN, however, completely prevented this decline in renal tissue (C). One-way ANOVA was used to compare groups with a post hoc 2-tailed Student’s t or Mann-Whitney test if statistically significant (P < 0.05). Data are represented using box-and-whisper plots, with boxes representing the IQR, lines representing the median value, and whiskers representing minimum and maximum values. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.