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

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.

Modulation of the Protein Kinase Cδ Interaction with the “d” Subunit of F1F0-ATP Synthase in Neonatal Cardiac Myocytes

“…Mitochondrial mechanisms involving protein kinase C (PKC) isozymes in cardiac PC and IR injury have received considerable attention (17)(18)(19)(20)(21). Identification of the particular isozyme(s) that is involved in these responses is an essential prerequisite for the development of clinically useful pharmacological mimetic agents.…”

Delta Protein Kinase C Interacts with the d Subunit of the F1F0 ATPase in Neonatal Cardiac Myocytes Exposed to Hypoxia or Phorbol Ester

“…Recently, mitochondrial mechanisms involving protein kinase C (PKC) isozymes in cardiac preconditioning (PC) and IR injury have received considerable attention (10). For example, ⑀PKC has been reported to activate mitochondrial ATPsensitive K ϩ channels (11), inhibit the opening of the mitochondrial permeability transition pore (12), induce the phosphorylation of the BAD protein to inhibit apoptosis in diabetic hearts (13), regulate anti-apoptotic activity through the regulation of Bcl-2 family of proteins (14), and enhance the activity of cytochrome c oxidase in PC (15,16).…”

Differential loss of cytochrome-coxidase subunits in ischemia-reperfusion injury: exacerbation of COI subunit loss by PKC-ε inhibition

“…More than 20 years of intense study have revealed numerous mechanisms by which PC protects the myocardium, including modest elevation of reactive oxygen species (ROS) (23,39,49,58), nitric oxide (23,58), mitochondrial ATP-sensitive potassium (mKATP) channels (18,31,32,39,60), heat shock proteins (18,34), and activation of protein kinase cascades (17). Protein kinase C (PKC) isozyme-induced alterations in mitochondrial functions also have been proposed to play important roles in cardiac PC (45). For example, the PKC-ε isozyme has been reported to form signaling clusters inside cardiac mitochondria with MAP kinase (4) and tyrosine kinases (56), inhibit the opening of the mitochondrial permeability transition pore (3), preserve cytochrome oxidase (CO) activity (16,47,48), and act in a cascade involving PKG-mediated opening of the mKATP channel (13).…”

“…Previously, Prabu et al (51) reported impaired CO function following I/R injury in isolated rabbit hearts involving PKA-mediated phosphorylation and degradation of CO I, IVi, and Vb subunits. However, there have been few cardiac studies exploring the regulation of CO following PC and even fewer exploring its regulation by individual PKC isozymes (16,45,47,48). Our laboratory recently demonstrated that PKC-ε coimmunoprecipitates with the number IV subunit of CO (COIV), which correlates with elevated CO activity during cardiac PC (16,48).…”