title: Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5'-triphosphate synthase activity.
abstract: OBJECTIVE
  Increasing evidence points to the role of mitochondrial dysfunction in the pathogenesis of sepsis. Previous data indicate that mitochondrial function is affected in monocytes from septic patients, but the underlying mechanisms and the impact of these changes on the patients' outcome are unknown. We aimed to determine the mechanisms involved in mitochondrial dysfunction in peripheral blood mononuclear cells from patients with septic shock.
  
  
  METHODS
  A cohort of patients with septic shock to study peripheral blood mononuclear cell mitochondrial respiration by high-resolution respirometry analyses and to compare with cells from control subjects.
  
  
  METHODS
  Three intensive care units and an academic research laboratory.
  
  
  METHODS
  Twenty patients with septic shock and a control group composed of 18 postoperative patients without sepsis or shock.
  
  
  METHODS
  Ex vivo measurements of mitochondrial oxygen consumption were carried out in digitonin-permeabilized peripheral blood mononuclear cells from 20 patients with septic shock taken during the first 48 hrs after intensive care unit admission as well as in peripheral blood mononuclear cells from control subjects. Clinical parameters such as hospital outcome and sepsis severity were also analyzed and the relationship between these parameters and the oxygen consumption pattern was investigated.
  
  
  RESULTS
  We observed a significant reduction in the respiration specifically associated with adenosine-5'-triphosphate synthesis (state 3) compared with the control group (5.60 vs. 9.89 nmol O2/min/10(7) cells, respectively, p < .01). Reduction of state 3 respiration in patients with septic shock was seen with increased prevalence of organ failure (r = -0.46, p = .005). Nonsurviving patients with septic shock presented significantly lower adenosine diphosphate-stimulated respiration when compared with the control group (4.56 vs. 10.27 nmol O2/min/10(7) cells, respectively; p = .004). Finally, the presence of the functional F1Fo adenosine-5'-triphosphate synthase complex (0.51 vs. 1.00 ng oligo/mL/10(6) cells, p = .02), but not the adenine nucleotide translocator, was significantly lower in patients with septic shock compared with control cells.
  
  
  CONCLUSIONS
  Mitochondrial dysfunction is present in immune cells from patients with septic shock and is characterized as a reduced respiration associated to adenosine-5'-triphosphate synthesis. The molecular basis of this phenotype involve a reduction of F1Fo adenosine-5'-triphosphate synthase activity, which may contribute to the energetic failure found in sepsis.
authors.affiliation: Intensive Care Unit, Instituto de Pesquisa Clínica Evandro Chagas, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: André M
authors.initials: AM
authors.lastname: Japiassú
authors.forename: Ana Paula S A
authors.initials: AP
authors.lastname: Santiago
authors.forename: Joana da Costa P
authors.initials: JC
authors.lastname: d'Avila
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Garcia-Souza
authors.forename: Antonio
authors.initials: A
authors.lastname: Galina
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro Faria-Neto
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Bozza
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Oliveira
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D016022:Case-Control Studies; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D012016:Reference Values; D012772:Shock, Septic / Q000097:blood* / Q000201:enzymology
chemical_list: C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases