Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

Myocardial injury is increased in the aged heart following ischemia and reperfusion (I-R) in both humans and experimental models. Hearts from aged 24-month-old Fischer 344 rats sustain greater cell death and decreased contractile recovery after I-R compared with 6-month-old adult controls. Cardiac mitochondria incur damage during I-R contributing to cell death. Aged rats have a defect in complex III of the mitochondrial electron transport chain (ETC) localized to the interfibrillar population of cardiac mitochondria (IFM), situated in the interior of the cardiomyocyte among the myofibrils. The defect involves the quinol oxidation site (Qo) and increases the production of reactive oxygen species (ROS) in the baseline state. Ischemia further decreases complex III activity via functional inactivation of the iron-sulfur subunit. We studied the contribution of ischemia-induced defects in complex III with the increased cardiac injury in the aged heart. The reversible blockade of the ETC proximal to complex III during ischemia using amobarbital protects mitochondria against ischemic damage, removing the ischemia component of mitochondrial dysfunction. Reperfusion of the aged heart in the absence of ischemic mitochondrial damage decreases net ROS production from mitochondria and reduces cell death. Thus, even despite the persistence of the age-related defects in electron transport, protection against ischemic damage to mitochondria can reduce injury in the aged heart. The direct therapeutic targeting of mitochondria protects against ischemic damage and decreases cardiac injury during reperfusion in the high risk elderly heart.