MiPsummer Programme pdf - Mitochondrial Physiology Society
MiPsummer Programme pdf - Mitochondrial Physiology Society
MiPsummer Programme pdf - Mitochondrial Physiology Society
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53<br />
Abstract # 24<br />
Reperfusion-induced mitochondrial dysfunction in the porcine heart is reduced by TRO40303<br />
in the area at risk predominantly through preservation of outer mitochondrial membrane<br />
intactness<br />
M.J. Hansson 1, 2 , S. Morota 1 , S. Koul 3 , R. Jablonowski 2 , J. van der Pals 3 , M. Kanski 2 , P. Gilje 3 , H.<br />
Engblom 2 and D. Erlinge 3 .<br />
1. <strong>Mitochondrial</strong> Pathophysiology Unit, 2. Department of Clinical <strong>Physiology</strong> and 3. Department of<br />
Cardiology, Lund University, Lund, Sweden.<br />
Background Mitochondria are considered to play critical roles in cell death pathways following<br />
ischemia-reperfusion injury.<br />
Objectives The objective of the present study was to perform a functional assessment of<br />
mitochondria following ischemia-reperfusion injury of the porcine heart as well as to evaluate<br />
mitochondrial effects of hypothermia and the outer membrane translocator protein (TSPO) ligand<br />
TRO40303.<br />
Methods Pigs were subjected to 40 min occlusion of the left anterior descending artery followed by<br />
4 hours of reperfusion [1]. Three groups of pigs were treated either by administration of 15 mg/kg<br />
TRO40303 or the same volume of saline (1 ml/kg) at normothermia 5 min before reperfusion, or by<br />
hypothermia (32°C) initiated prior to occlusion, n=8 for all groups. Transmural needle biopsies<br />
were taken from the non-ischemic area in the left lateral wall, from the area at risk in the<br />
midventricular anterior wall and from the ischemic core area in the apical anterior wall.<br />
<strong>Mitochondrial</strong> respiratory function was evaluated polarographically in skinned heart fibers using<br />
specific substrates and inhibitors [2,3]. In the control group, heart fibers from both ischemic areas<br />
demonstrated a general reduction of respiratory states. However, respiration linked to respiratory<br />
complex I was more affected than that to complex II indicating loss of soluble matrix components<br />
such as NAD(H). Addition of exogenous cytochrome c (CytC) increased the level of respiration<br />
several fold in both ischemic areas indicating increased permeability of the outer membrane and<br />
that CytC loss contributed to the reduced levels of respiration. These changes were diminished by<br />
hypothermia in both ischemic areas. TRO40303 attenuated inhibition of respiration involving<br />
complex II and reduced the stimulatory effects of CytC in the area at risk, but did not significantly<br />
reduce the altered ratio of complex I- and II-mediated respiration, and was without effect in the<br />
ischemic core area.<br />
Conclusion It is concluded that mitochondria in both the ischemic core area and the area at risk<br />
undergo significant alterations in respiratory function following ischemia-reperfusion injury<br />
consistent with both inner and outer mitochondrial membrane permeabilization which can be<br />
inhibited by hypothermia initiated prior to occlusion. Administration of TRO40303 prior to<br />
reperfusion appears to reduce reperfusion-induced mitochondrial dysfunction in the area at risk<br />
mainly by preserving outer membrane intactness and limiting CytC release.<br />
References 1. Gotberg M, Olivecrona GK, Engblom H, Ugander M, van der Pals J, et al. (2008) Rapid shortduration<br />
hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular<br />
obstruction and myocardial infarct size. BMC Cardiovasc Disord 8: 7.<br />
2. Veksler VI, Kuznetsov AV, Sharov VG, Kapelko VI, Saks VA (1987) <strong>Mitochondrial</strong> respiratory parameters in<br />
cardiac tissue: a novel method of assessment by using saponin‐skinned fibers. Biochim Biophys Acta 892: 191‐<br />
196.<br />
3. Pesta D, Gnaiger E (2012) High‐resolution respirometry: OXPHOS protocols for human cells and permeabilized<br />
fibers from small biopsies of human muscle. Methods Mol Biol 810: 25‐58.