Mitochondria and Cancer: Warburg Addressed

Abstract

Otto Warburg recognized that cancer cells generate excessive lactate in the presence of oxygen (aerobic glycolysis). It now appears that this phenomenon is the product of two factors: a return to the more glycolytic metabolism of the embryo and alterations 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 electron transport 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 may be useful alternate targets for cancer therapeutics.

Mitochondria as Chi

“…Haplogroup H has been associated with protection against sepsis (Baudouin et al 2005) and U with increased serum IgE levels (Raby et al 2007). Finally, various haplogroups have been correlated with altered risk for particular cancers (Booker et al 2006;Bai et al 2007;Darvishi et al 2007), which augments recent observations of associations between mutations in mitochondrial genes, both nDNA and mtDNA, and cancer (Gottlieb and Tomlinson 2005;Wallace 2005a;Brandon et al 2006).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…One of the main physiological modifications that tumor cells undergo is their switch from OXPHOS to glycolysis, a process known as Warburg effect [91,92]. This metabolic switch, even in conditions of high-oxygen tension, allows tumor cells to sustain their rapid proliferation rate and to better survive under TME hypoxic conditions.…”

Cancer as a Metabolic Disease

“…Considerable controversy has surrounded the issue of mitochondrial function in cancer cells [18,29,30,33,34,[51][52][53][54][55][56][57]. Sidney Weinhouse and Britton Chance initiated much of this controversy through their critical evaluation of the Warburg theory and the role of mitochondrial function [33,34].…”