Mitochondria and Cancer: Warburg Addressed

Abstract

Otto Warburg recognized that cancer cells generate excessive lactate in the presence of oxygen (aerobic glycolysis). It nowappears that this phenomenon is the product of two factors: a return to the more glycolytic metabolism of the embryo andalterations in oxidative phosphorylation (OXPHOS) to increase mitochondrial reactive oxygen species (ROS) production.Alterations in the Ras-PI3K-Akt signal transduction pathway can result in induction of hexokinase II and its attachment to mitochondrial porin redirecting mitochondrial ATP to phosphorylate glucose and drive glycolysis. Furthermore, partial inhibition of OXPHOS by mitochondrial gene mutations (germ-line or somatic) can reduce electron flux through the electrontransport chain, increasing mitochondrial ROS production. The increased ROS mutagenizes nuclear proto-oncogenes (initiation)and drives nuclear replication (promotion), resulting in cancer. Therefore, hexokinase II and mitochondrial ROS maybe useful alternate targets for cancer therapeutics.