A Multivariate Metabolomics Method for Estimating Platelet Mitochondrial Oxygen Consumption Rates in Patients with Sepsis

Abstract

Background: Sepsis-induced alterations in mitochondrial function contribute to organ dysfunction and mortality. Measuring mitochondrial function in vital organs is neither feasible nor practical, highlighting the need for non-invasive approaches. Mitochondrial function may be reflected in the concentrations of metabolites found in platelets and whole blood (WB) samples. We proposed to use these as alternates to indirectly estimate platelet mitochondrial oxygen consumption rate (mOCR) in sepsis patients. Methods: We determined the relationships between platelet mOCR and metabolites in both platelets and WB, as measured by quantitative 1H-NMR metabolomics. The associations were identified by building multiple linear regression models with stepwise forward-backward variable selection. We considered the models to be significant with an ANOVA test (p-value ≤ 0.05) and a positive predicted-R2. Results: The differences in adjusted-R2 and ANOVA p-values (platelet adj-R2: 0.836 (0.0003), 0.711 (0.0004) vs. WB adj-R2: 0.428 (0.0079)) from the significant models indicate the platelet models were more associated with platelet mOCR. Conclusions: Our data suggest there are groups of metabolites in WB (leucine, acetylcarnitine) and platelets (creatine, ADP, glucose, taurine) that are associated with platelet mOCR. Thus, WB and platelet metabolites could be used to estimate platelet mOCR.

A New Role of NAP1L1 in Megakaryocytes and Human Platelets

“…This finding could be met with surprise since published studies indicate that the PDH complex is inhibited during sepsis, resulting in a switch from mitochondrial aerobic oxidation to cytoplasmic anaerobic glycolysis, a process known to contribute to the formation of lactic acid and intracellular acidosis, which can lead to intracellular Ca2 + overload, mitochondrial membrane damage [ 58 , 82 , 83 ]. Nevertheless, contrasting the general PDC-dependent metabolic reprogramming response in sepsis [ 58 , 84 , 85 ], several studies demonstrated that mitochondrial oxygen consumption in PLTs is increased in septic patients, and closely related to their survival rate [ 86 , 87 , 88 ]. Therefore, based on our observations, we speculate that due to its chaperone and potential shuttling function, NAP1L1 protein in septic PLTs could help stabilize the conformation of PDC-E2 molecules, and also mediate the known one-way transport [ 89 ] into the mitochondrial compartment.…”

Mitochondrial Respiration of Platelets: Comparison of Isolation Methods

“…Knowledge of functional PLT activity in these cases could help the prophylaxis of anticoagulant treatment and improve the patients’ quality of life. Therefore, analysis of mitochondrial respiration of PLT represents a promising approach [ 38 , 39 , 40 , 41 , 42 ]. Increased respiration of PLT isolated from the blood of septic patients correlates with activation of circulating proinflammatory cytokines [ 17 ].…”

Nuclear magnetic resonance spectroscopy reveals biomarkers of stroke recovery in a mouse model of obesity-associated type 2 diabetes

“…Peaks were assigned to metabolites with Chenomx NMR Suite 9.0 (Chenomx, Edmonton, Alberta, Canada) and previous publications [ 18–22 ] ( Figure 1 ). Peak amplitudes were considered to reflect metabolite concentrations, and z-scores of metabolites with VIP > 1 were used for pathway analysis in MetaboAnalyst 5.0 ( www.metaboanalyst.ca ), using the Kyoto Encyclopedia of Genes and Genomes (KEGG) as pathway library [ 23 ].…”