A mouse study explored how NMN protects the heart from the damaging effects of sepsis, a severe inflammatory response to infection that can harm organs.
Key Points
The study identified several benefits of NMN treatment during sepsis:
- Improved heart function
- Reduced mitochondrial free radicals, inflammation, and heart injury makers
- Corrected abnormal protein modifications and regulation
- Protected cellular cleanup systems
- Restored energy production
Effect of NMN on Heart Function During Sepsis Evaluated in Mice
Sepsis was induced in half of the mice (males, 2 months old) by injection of a bacterial toxin (LPS, 4 mg/kg, i.p.), while healthy controls received an injection of saline.
The mice were divided into treatment groups:
- Saline + Vehicle: Healthy mice, vehicle (i.p. Saline, single dose)
- Saline + NMN: Healthy mice, NMN (i.p. NMN 500 mg/kg, single dose)
- LPS + Vehicle: Septic mice, vehicle (i.p. Saline, single dose)
- LPS + NMN: Septic mice, NMN (i.p. NMN 500 mg/kg, single dose)
Heart function was assessed, and tissue samples were collected for analysis 4 hours after the LPS injection.
NMN Reduced Mitochondrial ROS, Inflammation, and Heart Injury
Heart scans showed that NMN treatment improved heart function in mice with LPS-induced sepsis.
Analysis of the heart tissue revealed that NMN boosted mitochondrial NAD+ levels and lowered the production of harmful free radicals triggered by sepsis.
“LPS injection induced a significant increase in mitochondrial H2O2 generation, which was prevented by NMN.”
This graph compares the production of ROS (harmful free radicals) in two groups of mice: healthy mice (left side, “Saline”) and mice with sepsis caused by LPS (right side, “LPS”).
In septic mice treated with a control solution (LPS, blue bar), ROS levels were significantly higher. However, in septic mice treated with NMN (LPS, red bar), this increase in ROS was prevented.
NMN Prevented Abnormal Protein Modifications
NAD+ is essential for Sirtuin 3, an enzyme that regulates proteins in the mitochondria by removing chemical tags (acetyl groups) that affect their function.
When NAD+ levels drop, Sirtuin 3 activity decreases, causing an accumulation of proteins with these tags, disrupting cellular function.
In this study, septic mice had higher levels of tagged proteins in their mitochondria, indicating reduced Sirtuin 3 activity, which was reversed when NAD+ levels were restored with NMN.
Cellular Cleanup Systems Maintained
The researchers discovered that the increased production of free radicals during sepsis disrupted the cell’s waste disposal system (lysosomes) and its recycling process (autophagy).
This led to inflammation, heart damage, and dysfunction in septic mice.
NMN treatment helped maintain the cell’s cleanup systems by:
- Preserving an essential lysosomal enzyme (cathepsin B)
- Reducing markers of abnormal cellular recycling (LC3BII and p62)
“Mitochondrial ROS promotes lysosomal dysfunction and subsequent aberrant autophagy in endotoxemia, which are abrogated by NMN.”
“LPS-induced mitochondrial ROS contributes to lysosomal dysfunction and aberrant autophagy in cardiomyocytes, an event that is inhibited by NMN.”
Energy Production Preserved by NMN
Sepsis disrupts ATP synthase, a critical component of the cell’s energy-producing machinery, impairing the production of ATP, the primary energy source for cells.
“Disruption of ATP synthase ensures ATP depletion which directly causes myocardial functional decline.“
This disruption happens because an important protein on ATP synthase (ATP5A1) becomes tagged with chemical markers (acetyl groups) that target it for degradation.
NMN counteracted this damage by preventing the acetylation of ATP5A1, preserving its levels in the mitochondria, and maintaining ATP production in the hearts of septic mice.
“The levels of acetylated ATP5A1 protein were elevated in endotoxemic hearts, which were reduced by NMN.”
“Consistent with the alteration of ATP5A1 protein levels, NMN preserved the ATP production in endotoxemic mouse hearts.”
Conclusion
This study demonstrated that NMN protected heart function in septic mice by reducing mitochondrial free radical production and correcting abnormal protein modifications in mitochondria.
NMN increased NAD+ levels, which are essential for Sirtuin 3, an enzyme that removes acetyl groups to regulate protein function.
“NAD deficiency may compromise Sirtuin 3 activity, thereby increasing the levels of acetylated proteins in mitochondria.”
“Boosting NAD with NMN reduces mitochondrial protein acetylation in endotoxemic hearts.”
NMN also preserved critical energy production by preventing the acetylation and degradation of ATP5A1, a key component of ATP synthase, ensuring ATP production.
“NMN prevents ATP5A1 reduction through its deacetylation thereby preserving ATP synthase activity and ATP production in endotoxemic hearts.”
Additionally, NMN restored the cell’s cleanup and recycling systems—lysosomes and autophagy—by reducing mitochondrial free radical production.
“Mitochondrial ROS promotes lysosomal dysfunction and subsequent aberrant autophagy in endotoxemia, which are abrogated by NMN.”