MiPsummer Programme pdf - Mitochondrial Physiology Society

70
Abstract # 39
Diverse and tissue specific mitochondrial response in a mouse model of sepsis-induced
multiple organ failure
M. Karlsson 1 , N. Hara 2 , S. Morata 1 , F. Sjovall 1 , M. J. Hansson 1 , H. Uchino 2 , E. Elmer 1
1. Mitochondrial Pathophysiology Unit, Lund University, Lund, Sweden
2. Department of Anesthesiology, Tokyo Medical University, Tokyo, Japan
Background The pathogenesis of sepsis-induced multiple organ failure is complex and our
understanding is incomplete. It has been shown that sepsis can induce brain mitochondrial
dysfunction by increased uncoupling of the oxidative phosphorylation system [1]. However we
have previously demonstrated increasing respiration in human platelets during the first week of
sepsis following admission to the intensive care unit [2].
Objectives The objective of the present study was to evaluate the early temporal dynamics of brain
and liver mitochondrial function in a mouse model of sepsis-induced multiple organ failure.
Methods The ethical committee at Tokyo Medical University (H-24013) approved the study. Sepsis
was induced by cecal ligation and puncture (CLP) and controls were sham operated. Using highresolution
respirometry (Oroboros Oxygraph-2k) brain and liver homogenates from 31 C57BL/6
mice were analyzed at either 6 h or 24 h. ROS-production was measured in brain samples using
fluorometry (Oroboros LED2 module). A substrate-uncoupler-inhibitor-titration protocol examined
the role of the individual complexes as well as the uncoupled maximal respiratory capacity not
restricted by phosphorylation. Citrate synthase was measured in the samples as a mitochondrial
marker.
Results The brain exhibited an early decreased respiratory efficiency, the 6-hour group showed an
increase in the LEAK state in septic mice (P = 0.037) and a trend to lower complex I function in the
sepsis group (P = 0.124) resulting in a decreased respiratory control ratio (P = 0.043). At the 24-
hour time point there was also a trend to lower complex I function in the sepsis group (P = 0.077)
and a non-significant increase in the LEAK state (P = 0.262) resulting in a decreased respiratory
control ratio
(P = 0.029). There was no difference in brain ROS-production between the groups. In the liver at
24-hours, there was an increased LEAK state in septic mice (P = 0,0007) as seen in brain
homogenates, however complex I and complex I+II function in liver homogenates from septic mice
was also increased (P = 0,0007 and P < 0.0001) compared to controls. There was no significant
increase in citrate synthase activity.
Conclusion The present study demonstrates a diverse and tissue specific mitochondrial response to
sepsis. The brain displays an early decreased respiratory control ratio; conversely the liver showed
increased OXPHOS capacity compared to controls at 24 hours. It should be noted that the liver
displayed a significant difference in the control groups between time-points, perhaps due to the
insult of a sham operation. This needs to be further evaluated before any final conclusions can be
made.
References
1. d'Avila, J.C., et al., Sepsis induces brain mitochondrial dysfunction. Critical care medicine, 2008. 36(6): p.
1925-32.
2. Sjovall, F., et al., Temporal increase of platelet mitochondrial respiration is negatively associated with clinical
outcome in patients with sepsis. Critical care, 2010. 14(6): p. R214.