Loss of thioredoxin 2 alters mitochondrial respiratory function and induces cardiomyocyte hypertrophy

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Abstract

Thioredoxin 2 (Trx2), as a member of the thioredoxin system in mitochondria, is involved in controlling mitochondrial redox state. However, the role of Trx2 in cardiac biology is not fully understood. In the present study, the expression of Trx2 is silenced in quiescent neonatal rat ventricular cardiomyocytes (NRVCs) and mitochondrial respiratory function and cardiomyocyte hypertrophy are assessed. The results show that Trx2 depletion does not induce significant cytotoxicity in quiescent NRVCs. Remarkably, Trx2 depletion results in cardiomyocyte hypertrophy as determined by increased cell size and protein synthesis. Furthermore, Trx2 depletion inhibits AMPK activity and AMPK activator reversed cellular hypertrophy. Trx2 depletion enhances mitochondrial ROS generation without impact on cellular ROS level. Trx2 depletion has no effect on mitochondrial biogenesis. Specifically, Trx2 depletion increases mitochondrial respiration flux and total ATP concentration under quiescent conditions. To decipher the relationship between ROS generation, mitochondrial respiration flux, and AMPK signaling, mitochondrial metabolism and ROS was specifically inhibited, and the results show that AMPK inactivation and hypertrophic response in Trx2-silenced cells is reversed by respiration blockers but not ROS scavenger. In conclusion, these results show that beyond mitochondrial ROS scavenging, Trx2 controls mitochondrial respiratory function in quiescent cardiomyocytes and is implicated in cardiomyocyte hypertrophy via AMPK signaling.

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