Aconitate hydratase, mitochondrial precursor (EC 18.104.22.168) (Aconitase) (Citrate hydro-lyase)
Aging is an independent risk factor for cardiovascular diseases, such as myocardial infarction due to ischemia-reperfusion injury (I/R) of the heart. Cytosolic thioredoxin (Trx) is a multifunctional redox protein which has antioxidant and protein disulfide reducing properties. We hypothesized that high levels of Trx will protect against multifactorial disease such as myocardial infarction due to I/R injury in aged mice. Aged mice overexpressing human Trx ([i]Trx-Tg[/i]), mice expressing redox-inactive mutant of human Trx ([i]dnTrx-Tg[/i]) and non-transgenic litter-mates ([i]NT)[/i] were subjected to I/R (60/30 min), and cardiac function, mitochondrial structure and function, and biogenesis involving PGC1α pathway were evaluated in these mice. While aged [i]Trx-Tg[/i] mice were protected from I/R-induced reduction in ejection fraction (EF) and fractional shortening (FS), had smaller infarct with decreased apoptosis and preserved mitochondrial function, aged [i]dnTrx-Tg[/i] mice showed enhanced myocardial injury and mitochondrial dysfunction. Further, [i]Trx-Tg[/i] mice were protected from I/R induced loss of PGC1α, ACO2, MFN1 and MFN2 in the myocardium. The [i]dnTrx-Tg[/i] mice were highly sensitive to I/R induced apoptosis. Overall, our study demonstrated that the loss of Trx redox balance in I/R in aged [i]NT[/i] or [i]dnTrx-Tg[/i] mice resulted in decreased PGC1α expression that decreased mitochondrial gene expression with increased myocardial apoptosis. High levels of Trx, but not mitochondrial thioredoxin (Trx-2) maintained Trx redox balance in I/R resulting in increased PGC1α expression via AKT/CREB activation upregulating mitochondrial gene expression and protection against I/R injury.