Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock
Carrie A. Sims, … , Antonio Davila Jr., Joseph A. Baur
Carrie A. Sims, … , Antonio Davila Jr., Joseph A. Baur
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e120182. https://doi.org/10.1172/jci.insight.120182.
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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 3

NMN preserves complex I–dependent mitochondrial respiration and enhances mitochondrial NAD content.

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NMN preserves complex I–dependent mitochondrial respiration and enhances...
Following 90 minutes of hemorrhagic shock, tissues were harvested 1 hour after resuscitation (with or without NMN 400 mg/kg). Mitochondria from kidney and liver tissue were freshly isolated and evaluated using high-resolution respirometry (log10 scale). In both tissues, a defect in respiration was noted when NAD-dependent substrates, such as palmitoylcarnitine (PC) and pyruvate/glutamate/malate (CI), were used. Pretreatment, and subsequent resuscitation, with NMN completely restored mitochondrial respiration in the kidney (A) and preserved respiration with CI substrates in the liver (B). Without NMN treatment, NAD content was preserved following resuscitation in the kidney (C) and increased in the liver (D). NMN treatment augmented mitochondrial NAD levels in both the sham and shocked states (C and D). n = 5–6 per treatment group. 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. We measured the mRNA expression of key enzymes in fatty acid metabolism, including carnitine palmitoyltransferase 1 (CPT1), long-chain fatty acid transport protein 1 (SLC27A1), enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (Ehhadh), very-long-chain acyl-CoA dehydrogenase (VLCAD), long-chain acyl-CoA dehydrogenase, (LCAD), and medium-chain acyl-CoA dehydrogenase (MACD). The expression of key transcripts related to fatty acid oxidation was decreased by hemorrhagic shock in both the liver and kidney, but NMN tended to restore a subset of these only in the kidney (E and F). 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, **P < 0.01, ***P < 0.001, ****P < 0.0001.