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How Metabolic Reprogramming in mitochondrial dysfunction underpins uncontrolled cell growth and migration in Cancer

last modified Feb 16, 2018 03:11 PM

Cancer cells reprogram their metabolism in order to support the high energetic demands that are a cost of uncontrolled Molecular Cell logogrowth. Amongst these metabolic changes, activation of glucose metabolism is chief. It is known that glucose is metabolised via glycolysis and then fully oxidised in the mitochondria. Research has now shown that mitochondria are impaired in several cancer types. However, to what extent mitochondrial dysfunction contributes to the tipping towards glycolysis remains unclear.

New research led by Dr Christian Frezza published in the journal Molecular Cell,  capitalises on a new cell based model of mitochondrial dysfunction to address this link. Researchers, for the first time, have shown that mitochondrial defects lead to a profound metabolic rewiring of glucose metabolism and activation of glycolysis.

They further go on to show that this crosstalk between dysregulated mitochondrial metabolism and glycolysis in fact impinges on another important cellular metabolite - Glutamine. Glutamine is the most abundant amino acid in human blood and it is widely used by cancer cells for their growth. Through their study the researchers illustrate how in  situations of mitochondrial damage the breakdown of glutamine is co-opted to replenish NADH, one of the most important cellular  messenger molecule for multiple energetic reactions, and how this is achieved by a pathway known as reductive carboxylation. This glutamine-dependent NADH supply is essential to drive the activation of glycolysis, which in turn can support cell migration – a defining hallmark of cancer.

This is the first time that a bridging molecule, glutamine, and a metabolic pathway has been identified that link the loss of mitochondrial function with a switch to using glucose for metabolic needs and an eventual progression to cancer. This evidence expands our understanding of the energetic reprogramming  associated with uncontrolled growth and cell migration and offers new opportunities for targeting cancers.

The study entitled NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction by Gaude et al. has been published in Molecular Cell on the 15th of February, 2018.