Donor Plasma Serine Levels and Its Connection to Heart Transplant Mitochondrial Dysfunction and Acute Rejection

PurposeBrain death causes mitochondrial impairment which has been linked to allograft injury, poor graft survival, and enhanced acute rejection following heart transplantation. Serine is essential for controlling mitochondrial metabolism, and a lack of it promotes mitochondrial fragmentation. Therefore, we investigated the levels of serine in brain death donor plasma and their association with cardiac allograft outcome. MethodsUsing a metabolomics approach, we profiled over 100 metabolites, including serine, from 84 brain-dead heart transplant donors, and 20 healthy blood donors. We performed prediction analysis to investigate the impact of metabolites on graft-related clinical outcomes after heart transplantation. Furthermore, we used a multiomics approach to correlate donor serine levels with donor plasma proteomic and metabolomic profiles and early graft transcriptomic factors related to mitochondrial health.ResultsIn brain-dead donors, the plasma serine level was significantly higher when compared to healthy controls (p-value <0.001). Donor plasma serine levels correlated with mitochondrial function-related donor plasma metabolites like choline and histidine, with donor plasma proteins like myeloperoxidase and phosphatidylinositol-4-Phosphate 3-Kinase, and with heart transplant myocardial transcripts like FUCA1, SYK, TOP2A, and VSIG4. In prediction analysis, low donor plasma serine levels were associated with an increased risk of acute rejection after heart transplantation (Figure 1 A, B, C). However, Donor plasma serine levels were not associated to graft-related mortality after transplantation (Figure 1D).ConclusionThe results of this study indicate that serine insufficiency may cause mitochondrial dysfunction, which could lead to organ injury. Serine and mitochondria appear to have potential as possible therapeutic targets in heart transplantation. Brain death causes mitochondrial impairment which has been linked to allograft injury, poor graft survival, and enhanced acute rejection following heart transplantation. Serine is essential for controlling mitochondrial metabolism, and a lack of it promotes mitochondrial fragmentation. Therefore, we investigated the levels of serine in brain death donor plasma and their association with cardiac allograft outcome. Using a metabolomics approach, we profiled over 100 metabolites, including serine, from 84 brain-dead heart transplant donors, and 20 healthy blood donors. We performed prediction analysis to investigate the impact of metabolites on graft-related clinical outcomes after heart transplantation. Furthermore, we used a multiomics approach to correlate donor serine levels with donor plasma proteomic and metabolomic profiles and early graft transcriptomic factors related to mitochondrial health. In brain-dead donors, the plasma serine level was significantly higher when compared to healthy controls (p-value <0.001). Donor plasma serine levels correlated with mitochondrial function-related donor plasma metabolites like choline and histidine, with donor plasma proteins like myeloperoxidase and phosphatidylinositol-4-Phosphate 3-Kinase, and with heart transplant myocardial transcripts like FUCA1, SYK, TOP2A, and VSIG4. In prediction analysis, low donor plasma serine levels were associated with an increased risk of acute rejection after heart transplantation (Figure 1 A, B, C). However, Donor plasma serine levels were not associated to graft-related mortality after transplantation (Figure 1D). The results of this study indicate that serine insufficiency may cause mitochondrial dysfunction, which could lead to organ injury. Serine and mitochondria appear to have potential as possible therapeutic targets in heart transplantation.