Protein kinase C epsilon affects mitochondrial function through estrogen-related receptor alpha.

Members of the protein kinase C (PKC) family have been implicated in controlling cell proliferation, differentiation, and motility. Many of these processes are energy demanding. How PKCs affect mitochondrial function to regulate energy production is not well defined. Using an inhibitor Gö6983 with broad specificity, we found that inhibiting PKCs reduced mitochondrial mass and altered mitochondrial function characterized by elevations in mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) levels. These alterations indicated that Gö6983 suppressed the activities of mitochondrial regulators such as estrogen-related receptor α (ERRα). Indeed, Gö6983 dose-dependently suppressed the expression levels of ERRα-target genes peroxisome proliferator-activated receptor α (PPARα) and medium-chain acyl-CoA dehydrogenase (MCAD). Conversely, PKC activator phorbol ester (PMA) enhanced the expression level of another ERRα-target gene pyruvate dehydrogenase kinase 4 (PDK4). This PMA-mediated induction of PDK4 was blunted by an ERRα inverse agonist XCT-790, suggesting that ERRα plays a role in mediating the effects of PKCs on mitochondrial function. By over-expressing constitutively active forms of PKCs, we found that PKCε preferentially stimulated the transcription activity of ERRα. Through mutating residues on ERRα, we established that this PKCε-induced ERRα activity involves threonine 106, serine 110, and threonine 124 of ERRα. Collectively, these pieces of evidence suggest that ERRα plays an important role down-stream of PKCε to regulate mitochondrial homeostasis.