title: Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect.
abstract: 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.
authors.affiliation: Department of Pathology, Tianjin Union Medical Center Tianjin, People's Republic of China.
authors.forename: Shiwu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA ; Breast Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA.
authors.forename: Chuanwei
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tianjin Union Medical Center Tianjin, People's Republic of China.
authors.forename: Zhenduo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tianjin Union Medical Center Tianjin, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Medical School Houston, TX 77030, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Mills
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston, TX, 77030, USA.
authors.forename: Zesheng
authors.initials: Z
authors.lastname: Liu
keywords: Mitochondrial bioredox; glucose metabolic pathway; glycolysis; mitochondrial dynamics; the Warburg effect