Thioredoxin protects mitochondrial structure, function and biogenesis in myocardial ischemia-reperfusion via redox-dependent activation of AKT-CREB- PGC1α pathway in aged mice.

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 (), mice expressing redox-inactive mutant of human Trx () and non-transgenic litter-mates ( 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 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 mice showed enhanced myocardial injury and mitochondrial dysfunction. Further, mice were protected from I/R induced loss of PGC1α, ACO2, MFN1 and MFN2 in the myocardium. The 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 or 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.