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.
Original language | English (US) |
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Pages (from-to) | 1265-1280 |
Number of pages | 16 |
Journal | American Journal of Cancer Research |
Volume | 5 |
Issue number | 4 |
State | Published - 2015 |
Externally published | Yes |
Keywords
- Glucose metabolic pathway
- Glycolysis
- Mitochondrial bioredox
- Mitochondrial dynamics
- The warburg effect
ASJC Scopus subject areas
- Oncology
- Cancer Research