Abstract
IntroductionMitochondrial dysfunction has been suggested as a contributing factor to the pathogenesis of sepsis-induced multiple organ failure. Also, restoration of mitochondrial function, known as mitochondrial biogenesis, has been implicated as a key factor for the recovery of organ function in patients with sepsis. Here we investigated temporal changes in platelet mitochondrial respiratory function in patients with sepsis during the first week after disease onset.MethodsPlatelets were isolated from blood samples taken from 18 patients with severe sepsis or septic shock within 48 hours of their admission to the intensive care unit. Subsequent samples were taken on Day 3 to 4 and Day 6 to 7. Eighteen healthy blood donors served as controls. Platelet mitochondrial function was analyzed by high-resolution respirometry. Endogenous respiration of viable, intact platelets suspended in their own plasma or phosphate-buffered saline (PBS) glucose was determined. Further, in order to investigate the role of different dehydrogenases and respiratory complexes as well as to evaluate maximal respiratory activity of the mitochondria, platelets were permeabilized and stimulated with complex-specific substrates and inhibitors.ResultsPlatelets suspended in their own septic plasma exhibited increased basal non-phosphorylating respiration (state 4) compared to controls and to platelets suspended in PBS glucose. In parallel, there was a substantial increase in respiratory capacity of the electron transfer system from Day 1 to 2 to Day 6 to 7 as well as compared to controls in both intact and permeabilized platelets oxidizing Complex I and/or II-linked substrates. No inhibition of respiratory complexes was detected in septic patients compared to controls. Non-survivors, at 90 days, had a more elevated respiratory capacity at Day 6 to 7 as compared to survivors. Cytochrome c increased over the time interval studied but no change in mitochondrial DNA was detected.ConclusionsThe results indicate the presence of a soluble plasma factor in the initial stage of sepsis inducing uncoupling of platelet mitochondria without inhibition of the electron transfer system. The mitochondrial uncoupling was paralleled by a gradual and substantial increase in respiratory capacity. This may reflect a compensatory response to severe sepsis or septic shock, that was most pronounced in non-survivors, likely correlating to the severity of the septic insult.
Highlights
Mitochondrial dysfunction has been suggested as a contributing factor to the pathogenesis of sepsis-induced multiple organ failure
Initial depletion of mitochondrial DNA and subsequent activation of mitochondrial biogenic factors and restoration of mtDNA copy number were seen in a murine model of sepsis [5] and recently, increased transcripts of mitochondrial biogenetic markers was associated with survival in patients with severe sepsis and septic shock [6]
In this study we demonstrate several alterations in platelet mitochondrial respiratory function during the course of the first week in patients admitted to the intensive care units (ICU) due to severe sepsis or septic shock
Summary
Mitochondrial dysfunction has been suggested as a contributing factor to the pathogenesis of sepsis-induced multiple organ failure. Restoration of mitochondrial function, known as mitochondrial biogenesis, has been implicated as a key factor for the recovery of organ function in patients with sepsis. Multiple organ failure (MOF) is the leading cause of death in patients with severe sepsis and septic shock [1]. Restoration of mitochondrial function has been suggested as a prerequisite in recovery from MOF. Initial depletion of mitochondrial DNA (mtDNA) and subsequent activation of mitochondrial biogenic factors and restoration of mtDNA copy number were seen in a murine model of sepsis [5] and recently, increased transcripts of mitochondrial biogenetic markers was associated with survival in patients with severe sepsis and septic shock [6]. A fall in mtDNA in mononuclear cells was recently shown in patients with sepsis [8] and a temporal increase of mtDNA in blood cells from septic patients has been associated with improved outcome [9]
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