Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain

// Jose M. Garcia-Heredia 1,2 and Amancio Carnero 1 1 Instituto de Biomedicina de Sevilla (IBIS), HUVR/CSIC/Universidad de Sevilla, Sevilla, Spain 2 Departamento de Bioquímica Vegetal y Biología Molecular, Facultad de Biología, Sevilla, Spain Correspondence to: Amancio Carnero, email: // Keywords : cancer, metabolic switch, Warburg’s hypothesis, mitochondrial respiration, mitochondrial respiratory chain Received : July 06, 2015 Accepted : September 23, 2015 Published : October 09, 2015 Abstract Otto Warburg observed that cancer cells derived their energy from aerobic glycolysis by converting glucose to lactate. This mechanism is in opposition to the higher energy requirements of cancer cells because oxidative phosphorylation (OxPhos) produces more ATP from glucose. Warburg hypothesized that this phenomenon occurs due to the malfunction of mitochondria in cancer cells. The rediscovery of Warburg’s hypothesis coincided with the discovery of mitochondrial tumor suppressor genes that may conform to Warburg’s hypothesis along with the demonstrated negative impact of HIF-1 on PDH activity and the activation of HIF-1 by oncogenic signals such as activated AKT. This work summarizes the alterations in mitochondrial respiratory chain proteins that have been identified and their involvement in cancer. Also discussed is the fact that most of the mitochondrial mutations have been found in homoplasmy, indicating a positive selection during tumor evolution, thereby supporting their causal role.