Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect

Shiwu Zhang; Chuanwei Yang; Zhenduo Yang; Dan Zhang; Xiaoping Ma; Mills, Gordon; Zesheng Liu
August 2015
American Journal of Cancer Research;2015, Vol. 5 Issue 4, p1265
Academic Journal
Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A "plumbing model" is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells.


Related Articles

  • Cortical gamma oscillations and mitochondrial dysfunction: food for thought in neurodegeneration? Cunningham, M. O. // Proceedings of the Physiological Society;2013, p211P 

    Mitochondria are a cell organelle responsible for the production of energy for cellular activities. This is done mainly by the formation of ATP through oxidative phosphorylation via the mitochondrial respiratory chain. Since neurons are highly active cells, it is not surprising that neurons...

  • Antioxidant activities of dithiol alpha-lipoic acid. Islam, M. T. // Bangladesh Journal of Medical Science;Jun2009, Vol. 8 Issue 3, p6 

    Alpha-lipoic acid, a dithiol compound derived from octanoic acid, which acts as a coenzyme for several redox reactions in almost all the tissue of the body. It retains its protective functions in both oxidized and reduced forms. Alpha-lipoic acid reduces oxidative stress by redox generation of...

  • Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges. Kimmy Su; Bourdette, Dennis; Forte, Michael // Frontiers in Physiology;Jul2012, Vol. 3, p1 

    Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including...

  • The Role of Mitochondria in Neurodegeneration. Gandhi, Sonia; Beskina, Olga A.; Abramov, Andrey Y. // Current Medical Literature: Neurology;2012, Vol. 28 Issue 4, p93 

    The article discusses the functions of mitochondria and its role in neurodegeneration. The mitochondrion is the major source of cellular energy and it produces adenosine triphosphate (ATP) through oxidative phosphorylation. Neurodegenerative disorders including Parkinson's disease (PD) and...

  • Comparative analysis of cytosolic and mitochondrial ATP synthesis in embryonic and postnatal hippocampal neuronal cultures. Surin, Alexander M.; Khiroug, Serguei; Gorbacheva, Lubov R.; Khodorov, Boris I.; Pinelis, Vsevolod G.; Khiroug, Leonard // Frontiers in Molecular Neuroscience;Jan2013, Vol. 5, p1 

    ATP in neurons is commonly believed to be synthesized mostly by mitochondria via oxidative phosphorylation. Neuronal mitochondria have been studied primarily in culture, i.e., in neurons isolated either from embryos or from neonatal pups. Although it is generally assumed that both embryonic and...

  • Antioxidant Properties of Nigella sativa. Alenzi, Faris Q.; Alsakran Altamimi, Mohammed A.; Kujan, Omar; Tarakji, Bassel; Tamimi, Waleed; Bagader, Omar; Al-Shangiti, Ali; Talohi, Abdulrahman N.; Alenezy, Awwad K.; Al-Swailmi, Farhan; Alenizi, Dhaifallah; Salem, Mohamed L.; Wyse, Richard K. H. // Journal of Molecular & Genetic Medicine (Library Publishing Medi;2013, Vol. 7 Issue 3, p1 

    Molecular oxygen (O2) is essential in all species for the production of energy within mitochondria; a process known as oxidative phosphorylation. The end products of this process include adenosine triphosphate (ATP), water (H2O) and carbon dioxide (CO2). In addition, very small amounts of...

  • Mitochondrial translation and cellular stress response. Suhm, Tamara; Ott, Martin // Cell & Tissue Research;Jan2017, Vol. 367 Issue 1, p21 

    Mitochondria are organelles critical for the functionality of eukaryotic cells. One of their most prominent functions is energy conversion, thereby producing most of the cellular ATP. Energy conversion relies on the oxidative phosphorylation system, an ensemble of large protein complexes that...

  • The process of mammalian mitochondrial protein synthesis. Mai, Nicole; Chrzanowska-Lightowlers, Zofia; Lightowlers, Robert // Cell & Tissue Research;Jan2017, Vol. 367 Issue 1, p5 

    Oxidative phosphorylation (OXPHOS) is the mechanism whereby ATP, the major energy source for the cell, is produced by harnessing cellular respiration in the mitochondrion. This is facilitated by five multi-subunit complexes housed within the inner mitochondrial membrane. These complexes, with...

  • Mitochondrial Respiration - An Important Therapeutic Target in Melanoma. De Moura, Michelle Barbi; Vincent, Garret; Fayewicz, Shelley L.; Bateman, Nicholas W.; Hood, Brian L.; Mai Sun; Suhan, Joseph; Duensing, Stefan; Yan Yin; Sander, Cindy; Kirkwood, John M.; Becker, Dorothea; Conrads, Thomas P.; Van Houten, Bennett; Moschos, Stergios J.; Santos, Janine // PLoS ONE;Aug2012, Vol. 7 Issue 8, Special section p1 

    The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics