What may excite the growing band of researchers who are studying the Warburg effect, and cancer metabolism more generally, is the way the study resolves a long-standing debate about how and why cells switch to glycolysis in the first place. Warburg speculated that cancer cells change over to glycolysis, which occurs in the cytoplasm, because the mitochondria, where oxygen-dependent ATP synthesis occurs, are defective. But the mitochondria of cancer cells appear to be mostly intact, which led many researchers to minimize the importance of the glycolytic switch.
The mitochondria do display an intriguing difference, however. Normally, mitochondria turn glucose into ATP through the oxygen-dependent process of oxidative phosphorylation (OXPHOS). This results in the expulsion of protons, which lowers the mitochondria's membrane potential. Curiously, the mitochondria of cancer cells exhibit a high membrane potential. Researchers suspected that was because the cells have switched to an alternative means of producing ATP, namely glycolysis, but it was not clear if the glycolytic and mitochondrial pathways were connected in this fashion.
It appears the two pathways are reciprocally linked. Fantin and her colleagues found that by shutting down the glycolytic pathway (through the knock down of LDHA), they could lower the mitochondrial membrane potential of tumor cells. What is more, oxygen consumption increased in the knockdown cells, suggesting they were reverting to the mitochondrial OXPHOS pathway--a kind of Warburg effect in reverse. "The findings provide us with an insight into a mechanism that had been suspected in the last six or seven decades," said Leder, John Emory Andrus professor and chair of the Department of Genetics at HMS.
Knocking out the glycolytic pathway could deliver a big blow to tumor cells. "LDHA could be one weak point tha
Source:Harvard Medical School