In vivo metabolic studies of glucose, ATP and 2,3‐DPG in β‐thalassaemia intermedia, heterozygous β‐thalassaemic and normal erythrocytes: ¹³C and ³¹P MRS studies

Abstract

13C and 31P magnetic resonance spectroscopy was used to characterize the in vivo kinetics of glucose metabolism and intracellular ATP and 2,3-DPG concentrations in erythrocytes obtained from beta-thalassaemia intermedia, heterozygous beta-thalassaemic and normal individuals and maintained in suspension. Except for an upfield chemical shift in the 2P and 3P resonance of 2,3-DPG in the thalassaemia intermedia erythrocytes, the 31P spectra were comparable between all three blood types, showing similar concentrations of ATP (from 4.5 to 5.2 mumol/g Hb) and 2,3-DPG (from 17.2 to 19.7 mumol/g Hb). However, the profile of glucose metabolism was quite different in beta-thalassaemia intermedia erythrocytes, whereas glucose was consumed at a rate of 0.089 +/- 0.035 fmol/cell/h, significantly higher than that of normal (0.032 +/- 0.018 fmol/cell/h; P = 0.01) and heterozygous (0.025 +/- 0.004 fmol/cell/h; P = 0.01) erythrocytes. This near 3-fold faster rate of glucose metabolism in the thalassaemia intermedia erythrocytes could not be accounted for by any increase in glucose flux via the Embden-Meyerhof pathway, since no significant difference in 3-13C-lactate synthesis was observed among the three blood types (in units of fmol/cell/h, normal, 0.021 +/- 0.013; heterozygous, 0.021 +/- 0.006; beta-thalassaemia intermedia 0.045 +/- 0.025). These results reflect an accelerated rate of glucose metabolism in thalassaemia intermedia erythrocytes because the contribution of reticulocytes to this altered pattern of metabolism could be excluded. As the only other route of glucose metabolism in erythrocytes is the pentose phosphate pathway (PPP), these results indicate that the PPP is more active in beta-thalassaemia intermedia erythrocytes, perhaps as a consequence of their elevated intracellular oxidative state.

Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in β‐thalassaemia intermedia

“…A variety of metabolic dysfunctions have been reported in frequently transfused thalassaemia major patients (Vives‐Corrons et al , 1984; Ponnazhagan & Sarkar, 1992; Ting et al , 1994). Our data showed increased activity of most anti‐oxidant defence enzymes, increased basal flux of HMPS, and higher glucose consumption via the HMPS, whereas the relative stimulation after MB treatment was significantly lower.…”

“…Excess free α‐haemoglobin chains also influence RBC redox metabolism in β‐thalassaemia. Significantly increased activity of glucose‐6‐phosphate dehydrogenase (G6PD) and 6‐phosphogluconate dehydrogenase (6PGD) was observed in homozygous and heterozygous β‐thalassaemic patients (Vives Corrons et al , 1984; Ponnazhagan & Sarkar, 1992), whereas glucose consumption via glycolysis was remarkably increased in β‐thalassaemia intermedia RBC (Ting et al , 1994). However, no data are available on correlations between membrane damage, alteration of redox metabolism and induction of phagocytosis in this condition.…”

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

“…Erythropoiesis is a metabolically demanding process: erythroid maturation strictly depends on intracellular cyclic adenosine nucleotides and ATP, and mitochondrial biogenesis plays a crucial role in ATP generation (6)(7)(8)(9). Reduced ATP concentrations have been reported in β-thalassemic human red cells compared with healthy controls (10,11). Abnormal mitochondrial clearance in maturing erythroid cells from hemoglobin (Hb) E/β-thalassemia patients has also been described (12).…”

The Haldane malaria hypothesis: facts, artifacts, and a prophecy

“…Since both thalassemic and AS RBCs are microcytic, comparisons were performed between samples containing significantly higher numbers of mutant cells compared to nonmutant controls. In addition, thalassemic RBCs have a 3.5-fold higher glucose consumption, 23 and a reduced transport of adenosine. 24 Likewise, due to increased endogenous oxidative stress, lower NAD redox potential 25 and increased glycolysis, 26 AS RBCs also may have an increased metabolic rate.…”