Dynamic expression and localization of Protein Kinase A regulatory subunit RIα in cardiac mitochondria controls response to oxidative stress

Abstract

Recent studies have implicated many possible roles for protein kinase A (PKA) activity localized to mitochondria, especially in organs such as the heart with high metabolic activity and/or increased susceptibility to oxidative stress. Because mitochondria serve as a critical control point for cellular adaption to environmental stress, we hypothesize that regulation of mitochondrial‐localized PKA (mt‐PKA) modifies mitochondrial integrity and cellular homeostasis. In particular, we propose that PKA associated proteins are actively regulated in response to oxidative stress in order to modulate mt‐PKA activity. Using biochemical and proteomic analysis of differing mitochondrial subpopulations within cardiac tissue, we found a striking difference between the relative localization and expression of PKA and its associated proteins. By combining acute oxidative stress models, biochemical, microscopic and pharmacological assessment, as well as physiological and metabolic functional analysis methods, our data suggests that a stress‐induced loss of mitochondrial localized PKA RIα (mt‐RIα) is directly correlated to deterioration of mitochondria integrity, decrease in respiratory activity, increase in ROS production, and an overall reduction in cell viability and heart function. Therefore, we conclude that mt‐RIα is a necessary component for regulating mitochondrial response to oxidative stress. Support for this work was provided by HHMI and NIH funding.