Walker, for discovering the enzymatic mechanism(s), underpinning mitochondrial ATP synthesis ( 4– 7, 12– 16). In 1997, the Nobel Prize in Chemistry was jointly awarded to Paul D. Mitchell proposed that the asymmetric distribution of protons across a topologically enclosed membrane, plays an important role in mitochondrial ATP generation.

However, it wasn’t until 1961, that an American biochemist, namely Efraim Racker, first isolated the catalytic F1-subunit of the mitochondrial ATP-synthase. From 1939 to 1941, Fritz Lipmann, a German-born scientist, was the first to demonstrate that ATP is used as the universal chemical energy in cells. Then, in 1937, Herman Kalckar, from Denmark, showed that ATP synthesis is driven by cell respiration. Historically, ATP was initially discovered in 1929, by Karl Lohmann, a German chemist ( Figure 1). Viruses also energetically require sufficient ATP levels, for replication in host cells. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.ĪTP, the Energetic Currency of Life: History, Chemistry and BiologyĪTP is the vital energetic “currency” of all living things, including micro-organisms ( 1– 11). Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Therefore, we propose that the “energetically fittest” cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. 2The Department of Pharmacy, Health and Nutritional Sciences, The University of Calabria, Cosenza, Italy.1Translational Medicine, School of Science, Engineering and Environment (SEE), University of Salford, Greater Manchester, United Kingdom.Marco Fiorillo 1,2, Béla Ózsvári 1, Federica Sotgia 1* and Michael P. Repurposing Bedaquiline to Prevent ATP Production, Cancer Cell Motility, and Spontaneous Metastasis In Vivo: Targeted Down-Regulation of ATP5F1C.Defining a Metastasis Gene Signature, Using Bioinformatics: Validating the Importance of ATP5F1C, Using Several Independent Data Sets and MDA-MB-231 Cells.Tumor Dormancy and Multi-Drug Resistance: Are They Inter-Related?.Survival of the “Fittest”: ATP-High Cancer Cells Show a Multi-drug Resistant Phenotype, With Enhanced Anti-oxidant Capacity.Using ATP as a Biomarker to Metabolically Fractionate the Cancer Cell Population: Implications for ATP-Depletion Therapy.ATP, the Energetic Currency of Life: History, Chemistry and Biology.The editor and reviewer's affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Salk Institute for Biological Studies, United States

Atp production