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.

Methane-Rich Saline: A Potential Resuscitation Fluid for Hemorrhagic Shock

“…We followed the methods of Sims et al [10]. RNA from the heart, liver, and kidney was extracted from frozen tissue using TRIzol (MilliporeSigma) with ethanol precipitation.…”

Autophagy mitigates ethanol-induced mitochondrial dysfunction and oxidative stress in esophageal keratinocytes

“…Cells were treated with either 0% or 2% EtOH for 8 h and were re-suspended at a concentration of 1.0 x 10 6 /ml in pre-warmed MIRO5 respiration buffer, containing 110 mM mannitol, 0.5 mM EGTA, 3 mM MgCl 2 , 20 mM taurine, 10 mM KH 2 PO 4 , 60 mM K-lactobionate, 0.3 mM dithiothreitol, and 0.1% fatty acid-free bovine serum albumin at pH7.2. A standard substrate/inhibitor titration protocol was used for functional analysis of esophageal cell respiratory function [24]. The cells were subjected to the respirometer and after stabilization the baseline oxygen consumption were measured using high-resolution respirometry at 37˚C with constant stirring on the Oxygraph-2k FluoRespirometer (Oroboros Instruments, Innsbruck, Austria), then were permeabilized with 3-4 μl of 1 μg/μl digitonin and allowed to stabilize for 5 min.…”

NAD+ flux is maintained in aged mice

“…The mitochondrial NAD + pool is distinct, as evidenced by several studies indicating that the organelles can retain their NAD + at least transiently when nuclear and cytosolic NAD + are depleted (C.A. Sims, 2018;Pittelli M, 2010;Yang H, 2007 ). We have previously demonstrated ongoing import of NAD + into mitochondria using heavy isotope labeling methods , and shown that chronic lowering of NAD + concentration in skeletal muscle has a corresponding effect on NAD + concentration in the mitochondria (Frederick DW, 2016).…”