Abstract
Little evidence has been available on the oxidative pathways of glutamine and glutamate, the major respiratory substrates of cancer cells. Glutamate formed from glutamine by phosphate-dependent glutaminase undergoes quantitative transamination by aerobic tumor mitochondria to yield aspartate. However, when malate is also added there is a pronounced decrease in aspartate production and a large formation of citrate and alanine, in both state 3 and 4 conditions. In contrast, addition of malate to normal rat heart, liver, or kidney mitochondria oxidizing glutamate causes a marked increase in aspartate production. Further analysis showed that extramitochondrial malate is oxidized almost quantitatively to pyruvate + CO2 by NAD(P)+-linked malic enzyme, present in the mitochondria of all tumors tested, but absent in heart, liver, and kidney mitochondria. On the other hand intramitochondrial malate generated from glutamate is oxidized quantitatively to oxalacetate by mitochondrial malate dehydrogenase of tumors. Acetyl-CoA derived from extramitochondrial malate via pyruvate and oxalacetate derived from glutamate via intramitochondrial malate are quantitatively converted into citrate, which is extruded. No evidence was found that malic enzyme of tumor mitochondria converts glutamate-derived malate into pyruvate as postulated in other reports. Possible mechanisms for the integration of mitochondrial malic enzyme and malate dehydrogenase activities in tumors are discussed.
Highlights
Little evidence has been available on the oxidative energy source forHeLa cells even inthe presence of physiopathways of glutamineand glutamate, themajor res- logical levelsof glucose [4]
Additionof malate to normal rat heart,liver, or kidneymitochondria oxidizing glutamatecausesa markedincreaseinaspartateproductionF. urther analysisshowed that extramitochondrial malaitseoxcast some doubt on the essentiality of the conversion of glucose to lactate by aerobicglycolysisfor tumor cells, hexoses are still required for continual cell growth,apparently as anabolicprecursors, of ribose (9,ll-13)
This paper describes an extensive investigation of the pathway(s) of glutamine and glutamate oxidation in mitochondriafrom ascites tumor cells, whichare shown to differ substantially from the pathways promoted by mitochondria from normal cells
Summary
Little evidence has been available on the oxidative energy source forHeLa cells even inthe presence of physiopathways of glutamineand glutamate, themajor res- logical levelsof glucose [4]. Urther analysisshowed that extramitochondrial malaitseoxcast some doubt on the essentiality of the conversion of glucose to lactate by aerobicglycolysisfor tumor cells, hexoses are still required for continual cell growth,apparently as anabolicprecursors, of ribose (9,ll-13). These considerationshave focusedattention on other fuels for energyproduction in tumor cells and have idizedalmostquantitatively to pyruvate CO, by pointed to glutamine as the major respiratory. NAD(P)+-linkedmalicenzyme,presentinthemitosubstrate in all malignant cell lines investigated to date It chondria oaf ll tumors tested, but abseinntheart, liver, may alsobe noted that glutamineis the most abundant amino and kidney mitochondria.On the otherhand intrami- acid in both blood plasmaand in optimal culture media [12].
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