The transient, reversible blockade of electron transport (BET) during
ischemia or at the onset of reperfusion protects mitochondria and decreases cardiac injury.
Apoptosis inducing factor (AIF) is located within the mitochondrial intermembrane space. A release of AIF from mitochondria into cytosol and nucleus triggers
caspase-independent cell death. We asked if BET prevents the loss of AIF from mitochondria as a mechanism of protection in the
buffer perfused heart. BET during
ischemia with
amobarbital, a rapidly reversible inhibitor of mitochondrial complex I, attenuated a release of AIF from mitochondria into cytosol, in turn decreasing the formation of cleaved and activated PARP-1. These results suggest that BET-mediated protection may occur through prevention of the loss of AIF from mitochondria during
ischemia-reperfusion. In order to further clarify the role of mitochondrial AIF in BET-mediated protection, Harlequin (Hq) mice, a genetic model with mitochondrial AIF deficiency, were used to test whether BET could still decrease cell injury in Hq mouse hearts during reperfusion. BET during
ischemia protected Hq mouse hearts against
ischemia-reperfusion injury and improved mitochondrial function in these hearts during reperfusion. Thus, cardiac injury can still be decreased in the presence of down-regulated mitochondrial AIF content. Taken together, BET during
ischemia protects both hearts with normal mitochondrial AIF content and hearts with mitochondrial AIF deficiency. Although preservation of mitochondrial AIF content plays a key role in reducing cell injury during reperfusion, the protection derived from the BET is not fully dependent on AIF-driven mechanisms.