SIRT3 attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. [Molecular Bases of Disease]

March 10th, 2015 by Cheung, K. G., Cole, L. K., Xiang, B., Chen, K., Ma, X., Myal, Y., Hatch, G. M., Tong, Q., Dolinsky, V. W.

Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin, and causing inefficient electron transfer resulting in the production of reactive oxygen species (ROS). Sirtuin-3 (SIRT3) is a class III lysine deacetylase that is localized to the mitochondria and regulates mitochondrial respiration and oxidative stress resistance enzymes such as superoxide dismutase-2 (SOD2). The purpose of this study was to determine whether SIRT3 prevents DOX-induced mitochondrial ROS production. Administration of DOX to mice suppressed cardiac SIRT3 expression and DOX induced a dose-dependent decrease in SIRT3 and SOD2 expression in H9c2 cardiomyocytes. SIRT3 null mouse embryonic fibroblasts produced significantly more ROS in the presence of DOX compared to wild-type cells. Overexpression of wild-type SIRT3 increased cardiolipin levels and rescued mitochondrial respiration and SOD2 expression in DOX treated H9c2 cardiomyocytes and attenuated the amount of ROS produced following DOX-treatment. These effects were absent when a deacetylase deficient SIRT3 was expressed in H9c2 cells. Our results suggest that overexpression of SIRT3 attenuates DOX-induced ROS production and this may involve increased SOD2 expression and improved mitochondrial bioenergetics. SIRT3 activation could be a potential therapy for DOX-induced cardiac dysfunction.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on SIRT3 attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. [Molecular Bases of Disease]