Is absence of pyruvate dehydrogenase complex in mitochondria a possible explanation of significant aerobic glycolysis by normal human leukocytes?

Abstract

The oxygen consumption of leukocyte mitochondria of both healthy donors and leukemic patients was tested by using different respiratory substrates. The results indicate that pyruvate could not be utilized by mitochondria of normal leukocytes, whereas mitochondria of leukemic leukocytes could use pyruvate as a good respiratory substrate. A search for the possible presence of pyruvate dehydrogenase complex (PDC) in leukocytes indicates that this enzyme is apparently absent in mitochondria of normal leukocytes but is quite active in mitochondria of leukemic leukocytes. The absence of PDC in normal leukocyte mitochondria can explain the phenomenon of significant aerobic glycolysis that has been observed in normal leukocytes.z 1998 Federation of European Biochemical Societies.

Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism

“…The concentrations of AICA compounds used in these experiments ranged between 10 and 100 μM, which can be achieved in lymphoblasts exposed to only 20 nM MTX (Bokkerink et al, 1986;Bokkerink et al, 1988), or in inflammatory cells of animals treated with low-dose MTX (Cronstein et al, 1994;Cronstein et al, 1993;Gadangi et al, 1996). Glycolysis is an important energy-producing pathway for the immune system since leukocytes do not have an active pyruvate dehydrogenase complex; thus, energy derived from the Krebs cycle cannot be obtained using glucose as the metabolic fuel (Biswas et al, 1998;Haji-Michael, et al, 1999). In cell culture experiments, AICA riboside potentiated MTX toxicity in neoplastic T cells, an analogous finding to its potentiation of MTX efficacy in rat AA that we report here (Ha and Baggott, 1994).…”

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

“…Leukocytes in particular have limited mitochondria and when they are activated, as they are in wounds, they derive most of their energy from glycolysis thus releasing large amounts of lactate regardless of oxygen concentration (7,26). Transient inflammation is an obligatory precursor to wound healing.…”

“…One of the few axioms of wound healing is "no inflammation, no healing". Furthermore, the recent enthusiasm for hypoxia-generated angiogenic signals seems to have obscured the fact that hypoxia impairs collagen synthesis and deposition, both of which are required for angiogenesis (7). No matter how much angiogenic stimulant is present, the functional response cannot proceed in severe hypoxia because new vessels require collagen for strength to withstand the pressures of blood flow.…”

“…Neither can wounds resist bacterial infection at that level of pO 2 (3). Without collagen, angiogenesis cannot proceed beyond the stage of fragile endothelial buds (7). The problem of decreased collagen deposition in angiogenesis is illustrated by scurvy (ascorbate deficiency) that impairs hydroxylation of collagen, prevents collagen deposition, interferes with angiogenesis, and severely depresses wound healing by producing precisely the same lesion as hypoxia (30).…”

Membrane tubulovesicular extensions (cytonemes)

“…8,27,28,36 Similar to malignant cells, leukocytes possess a high rate of glycolysis, even in the presence of oxygen. 37 The extrusion of TVEs from the cells occurred upon neutrophil adhesion to the fibronectin-coated substrata in the presence of iodoacetic acid, an inhibitor of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or phloretin, an inhibitor of facilitative glucose transporters. The inhibition of oxidative phosphorylation did not induce the formation of membrane extensions.…”