Cross talk between mitochondria and NADPH oxidases

Abstract

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.

Figure 1

Interaction of various sources of reactive oxygen species ROS. The production of ROS from any one source can lead to activation of the NADPH oxidases, conversion of xanthine dehydrogenase to xanthine oxidase, can stimulate the production of mitochondrial ROS or result in uncoupling of the endothelial nitric oxide synthase (eNOS).

Figure 2

Schematic presentation of the mitochondrial electron transport chain and production of mitochondrial ${{\mathrm{O}}_2}^{\underset{‒}{•}}$.

Figure 3

Structural homology of the vascular NADPH oxidases.

Figure 4

Proposed crosstalk between mitochondria and NADPH oxidases.