Modulation of Mitochondrial Protein Kinase C Isozymes: A New Therapeutic Frontier?

Tiffany      Nguyen; Mourad      Ogbi; Dehuang      Guo; John   A.   Johnson

Abstract

Alterations in protein kinase C (PKC) isozymes and mitochondrial functions such as oxidative phosphorylation (OXPHOS) and apoptosis have each been implicated in human diseases. However, relatively little is currently understood regarding the physiologic roles of individual PKC isozymes or their substrates for phosphorylation in mitochondria. Recent advances in mitochondrial localization of PKC isozymes and methods of PKC isozyme-selective inhibition have made possible a more focused pursuit of these relationships. Studies of PKC isozyme involvement in areas such as mitochondrial ROS production, antioxidant defense, energetics, and apoptosis are now possible and hold the potential to provide promising pharmaceuticals for therapies against cardiovascular, diabetic, cancer and other diseases. The purpose of this review is to present the current state of knowledge illustrating a link between PKC isozymes, mitochondria and human disease. Novel strategies for PKC isozyme-selective inhibition will also be discussed with an emphasis on the rational targeting of mitochondrial PKC isozymes in research and clinical settings.

Keywords: Protein kinase C isozyme-selective inhibition, mitochondria, apoptosis, ROS, energetics, disease, antisense, pseudosubstrate, translocation inhibitors