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

Abstract

Myocardial injury is increased in the aged heart following ischemia and reperfusion (I-R) in both humans and experimental models. Hearts from aged 24 mo. old Fischer 344 rats sustain greater cell death and decreased contractile recovery after I-R compared to 6 mo. 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 to 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.

Translational Regulation of the Mitochondrial Genome Following Redistribution of Mitochondrial MicroRNA in the Diabetic Heart

“…Further, mice lacking specific miRNAs, including miR-378, exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity 22 . Though increasing evidence indicates that mitochondrial subpopulations are differentially influenced by physiological stressors 4, 23–26 , no study has reported specific enrichment patterns of mitomiRs in spatially-distinct subpopulations or whether distribution patterns are influenced by pathological states, including diabetes mellitus. The results of our studies suggest a dynamic system requiring the presence of RISC constituents in the mitochondrion, which function to regulate the mitochondrial genome during diabetic insult in a spatially-distinct manner.…”

Cardioprotective Effects of Combined Therapy with Hyperbaric Oxygen and Diltiazem Pretreatment on Myocardial Ischemia-Reperfusion Injury in Rats

“…ROS leads to damage of cell membranes, protein, DNA, and mitochondrial membrane potential (ΔΨm) [7]. The latter causes uncoupling and subsequently leads to hyperactivity of the ETC due to inefficient adenosine triphosphate (ATP) production [8,9]. Reduced ATP causes inhibition of the ATP-dependent sodiumpotassium pump (Na + -K + -ATPase), which further contributes to myocardial sodium loading [10].…”

Blockade of Electron Transport at the Onset of Reperfusion Decreases Cardiac Injury in Aged Hearts by Protecting the Inner Mitochondrial Membrane

“…Amobarbital given before ischemia also decreases cardiac injury in aged rat hearts measured after reperfusion [36]. These findings suggest that direct manipulation of mitochondrial function is an alternative approach to protect aged hearts that lack effective endogenous cytoprotective mechanisms.…”