Influence of Immune Cell Subtypes on Mitochondrial Measurements in Peripheral Blood Mononuclear Cells From Children with Sepsis

Weiss, Scott L.; Henrickson, Sarah E.; Lindell, Robert B.; Sartori, L.; Zhang, Donglan; Bush, Jenny; Farooqi, Sumera; Starr, Jonathan; Deutschman, Clifford S.; McGowan, Francis X.; Becker, Lance B.; Tuluc, Florin; Wherry, E. John; Picard, Martin; Wallace, Douglas C.

doi:10.1097/shk.0000000000001903

Cited by 7 publications

(6 citation statements)

References 38 publications

(53 reference statements)

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“…It is important to identify these changes in sepsis endotypes/phenotypes and does not preclude potential targets other than PDC as mediators of survival with DCA treatment. 52,53 Our present working theory is that investigating the cysteine thiol redox axis may identify time-sensitive biomarkers of the mitochondria energy supply chain shortage during sepsis. 51,54…”

Section: The Precise Molecular Mechanisms Underlying Energy Imbalance...mentioning

confidence: 99%

“…Undoubtedly, there is a remarkable breadth in sepsis‐induced responses and our observations implicate DCA resets the anabolism and catabolism energy imbalance throughout the septic host, not just innate immune cells. It is important to identify these changes in sepsis endotypes/phenotypes and does not preclude potential targets other than PDC as mediators of survival with DCA treatment 52,53 . Our present working theory is that investigating the cysteine thiol redox axis may identify time‐sensitive biomarkers of the mitochondria energy supply chain shortage during sepsis 51,54 …”

Section: The Precise Molecular Mechanisms Underlying Energy Imbalance...mentioning

confidence: 99%

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Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.

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Section: The Precise Molecular Mechanisms Underlying Energy Imbalance...mentioning

confidence: 99%

Section: The Precise Molecular Mechanisms Underlying Energy Imbalance...mentioning

confidence: 99%

Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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“…Moreover, mitochondrial function, which normally converts lactate into energy, is impaired by sepsis, potentially causes lactate accumulation and hyperlactatemia [ 28 ]. Inflammatory response can activate immune cells, which is another source of lactate in sepsis [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Association Between Lactate and 28-Day Mortality in Elderly Patients with Sepsis: Results from MIMIC-IV Database

Yang

Ding

et al. 2022

Infect Dis Ther

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Introduction This study aimed to explore the association of serum lactate with clinical outcomes in elderly patients with sepsis based on data from the MIMIC-IV database. Methods All elderly patients with sepsis (age ≥ 65 years) were included. Different models were constructed for exploring the relationships between lactate and 28-day mortality. A two-segment linear regression model was performed to verify the threshold effects of lactate on clinical outcomes and smooth curve fitting was performed. Results A total of 4199 elderly patients with sepsis were included. The 28-day mortality was 32.22% ( n = 1395). After adjustment for all potential cofounders, for each 1 mmol/l increment in lactate, the odds ratio (OR) of 28-day mortality was 1.23 (95% CI 1.18–1.28, P < 0.0001). Smooth fitting curves indicated a non-linear positive relationship between lactate and 28-day mortality. The turning point of lactate level was 5.7 mmol/l: at ≤ 5.7 mmol/l, with each 1 mmol/l increment in lactate, the risk of 28-day mortality increased significantly (OR 1.32, 95% CI 1.25–1.38, P < 0.0001); the significantly positive relationship was still present at lactate > 5.7 mmol/l (OR 1.10, 95% CI 1.04–1.18, P = 0.0019). The area under the ROC curve (AUC) of lactate was 0.618 (95% CI 0.599–0.635) and the cutoff value of lactate was 2.4 mmol/l with a sensitivity of 0.483 and a specificity of 0.687. Conclusion In elderly patients with sepsis, a non-linear positive relationship was discovered between serum lactate and 28-day mortality. Physicians should be alert to lactate assessment at admission and pay more attention to those patients with higher levels of lactate. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-022-00736-3.

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“…Factors in circulation have profound effects on not only the local tissue, but also on circulating cells. For example, it has recently been shown in pediatric sepsis that PBMC mitochondrial function is mostly correlated with T-lymphocyte CD4+/ CD8+ subtypes (36). Alternatively, mtDNA can cause mitochondrial dysfunction in macrophages in the context of ischemia reperfusion injury (37).…”

Section: Studies Of Burn Sepsis Diagnosis Have Examined a Variety Of ...mentioning

confidence: 99%

Diagnostic Value of Mitochondrial Dna and Peripheral Blood Mononuclear Cell Respirometry for Burn-Related Sepsis

Robles

Heard

Chao

et al. 2022

Shock

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Background: Sepsis is the leading cause of mortality among burn patients that survive acute resuscitation. Clinical criteria have poor diagnostic value for burn-induced sepsis, making it difficult to diagnose. Protein biomarkers (e.g., procalcitonin) have been examined with limited success. We aimed to explore other biomarkers related to mitochondria (mitochondrial DNA [mtDNA]) and mitochondrial function of peripheral blood mononuclear cells (PBMCs) for sepsis diagnosis in burn patients. Methods: We conducted a follow-up analysis of a single center, prospective observational study of subjects (n = 10 healthy volunteers, n = 24 burn patients) to examine the diagnostic value of mtDNA and PBMC respirometry. Patients were enrolled regardless of sepsis status and followed longitudinally. Patient samples were classified as septic or not based on empiric clinical criteria. Isolated PBMCs were loaded into a high-resolution respirometer, and circulating mtDNA was measured with a PCR-based assay. Sequential Organ Failure Assessment (SOFA) criteria were also compared. Results: The SOFA criteria comparing septic versus before/nonseptic patients revealed significantly higher heart rate (P = 0.012) and lower mean arterial pressure (P = 0.039) in burn sepsis. MtDNA was significantly elevated in septic burn patients compared with healthy volunteers (P < 0.0001) and nonseptic patients (P < 0.0001), with no significant difference between healthy volunteers and nonseptic burn patients (P = 0.187). The area under the ROC curve (AUC) for mtDNA was 0.685 (95% confidence interval = 0.50–0.86). For PBMC respirometry, burn patients exhibited increased routine and maximal respiration potential compared with healthy volunteers. However, no difference was found between nonseptic and septic patient samples. A subanalysis revealed a significant mortality difference in PBMC respirometry after sepsis diagnosis, wherein survivors had higher routine respiration (P = 0.003) and maximal respiration (P = 0.011) compared with nonsurvivors. Conclusion: Our findings reveal that mtDNA may have diagnostic value for burn sepsis, whereas PBMC respirometry is nonspecifically elevated in burns, but may have value in mortality prognosis. A larger, multisite study is warranted for further validity of the diagnostic value of mtDNA and PBMC respirometry as biomarkers for prognosis of sepsis and outcomes in burn patients.

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Influence of Immune Cell Subtypes on Mitochondrial Measurements in Peripheral Blood Mononuclear Cells From Children with Sepsis

Cited by 7 publications

References 38 publications

Sepsis, pyruvate, and mitochondria energy supply chain shortage

Sepsis, pyruvate, and mitochondria energy supply chain shortage

Association Between Lactate and 28-Day Mortality in Elderly Patients with Sepsis: Results from MIMIC-IV Database

Diagnostic Value of Mitochondrial Dna and Peripheral Blood Mononuclear Cell Respirometry for Burn-Related Sepsis

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