Patients with sepsis exhibit increased mitochondrial respiratory capacity in peripheral blood immune cells

Abstract

IntroductionIn sepsis, mitochondria have been associated with both initial dysfunction and subsequent upregulation (biogenesis). However, the evolvement of mitochondrial function in sepsis over time is largely unknown, and we therefore investigated mitochondrial respiration in peripheral blood immune cells (PBICs) in sepsis patients during the first week after admission to the intensive care unit (ICU).MethodsPBICs from 20 patients with severe sepsis or septic shock were analyzed with high-resolution respirometry 3 times after admission to the ICU (within 48 hours, days 3 to 4 and days 6 to 7). Mitochondrial DNA (mtDNA), cytochrome c (Cyt c), and citrate synthase (CS) were measured as indicators of cellular mitochondrial content.ResultsIn intact PBICs with endogenous substrates, a gradual increase in cellular respiration reached 173% of controls after 1 week (P = 0.001). In permeabilized cells, respiration using substrates of complex I, II, and IV were significantly increased days 1 to 2, reaching 137%, 130%, and 173% of controls, respectively. In parallel, higher levels of CS activity, mtDNA, and Cyt c content in PBICs (211%, 243%, and 331% of controls for the respective indicators were found at days 6 to 7; P < 0.0001). No differences in respiratory capacities were noted between survivors and nonsurvivors at any of the time points measured.ConclusionsPBICs from patients with sepsis displayed higher mitochondrial respiratory capacities compared with controls, due to an increased mitochondrial content, as indicated by increased mitochondrial DNA, protein content, and enzyme activity. The results argue against mitochondrial respiratory dysfunction in this type of cells in sepsis.

Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells in Pediatric Septic Shock*

“…For example, Belikova et al found that maximal oxygen consumption in the presence of uncoupler was decreased (though SRC was not explicitly calculated) and the fraction of LEAK respiration was increased compared to healthy controls (18). In contrast to these findings, however, Sjovall et al demonstrated a progressive increase in basal and maximal respiration in adult PBMCs on day 1–2 through day 6–7 of sepsis compared to healthy controls (21). These contradictory findings may stem from methodological variability between studies.…”

“…However, direct evidence for mitochondrial dysfunction in human studies is limited, largely due to the impracticality of tissue biopsies in critically ill patients (15, 16). Several studies have shown that alterations in mitochondrial respiration in peripheral blood mononuclear cells (PBMCs)—monocytes and lymphocytes--are associated with disease severity, immune suppression, and mortality (17–21). Under quiescent conditions, PBMCs rely more on mitochondrial respiration than glycolysis to meet metabolic demands and exhibit a substantial SRC (22–24).…”

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

“…In particular, the prominence of NADH dehydrogenase activity in the top gene networks is consistent with decreased complex I gene expression [56] and activity noted in skeletal muscle in human adult sepsis [57,58]. Prior studies using blood samples from patients with sepsis have also demonstrated altered respiratory chain activity in peripheral blood mononuclear cells and platelets [9,11,13,59,60].…”

In vitro diagnosis of sepsis: a review

“…35 Furthermore, mitochondrial dysfunction has been implicated as a possible causative mechanism for the reduced activity of immune cells in sepsis. 36 …”