At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

/pdf/free-radicals-in-the-physiological-control-of-cell-function-g3w3iyr0ph.pdf

Free Radicals in the Physiological Control of Cell Function

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

/pdf/how-mitochondria-produce-reactive-oxygen-species-4spvs9r9mw.pdf

How mitochondria produce reactive oxygen species.

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

Human mesenchymal stem cells modulate allogeneic immune cell responses

The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2−•). Even though O2−• is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7793.2003.00335.x

Mitochondrial formation of reactive oxygen species.

White et al.1 developed a process for preparing erythropoietin concentrate from the plasma of sheep which were made anemic with phenylhydrazine. They obtained an average yield of approximately 2,000 units of concentrate per sheep. We have been able to increase this yield to over 10,000 units per sheep by instituting a number of modifications in the procedures for preparing and treating animals and for processing the concentrate. The improvements make it possible to reduce the cost of preparing the concentrate and allow the preparation of quantities in the order of millions of units. Since it had been shown by White et a2.l that the erythropoietin concentration in blood rises steeply when the hematocrit falls below 15%, it seemed important to us to achieve conditions for reproducibly lowering the hematocrit below this level. To achieve this, we introduced a number of modifications in their method. Animals were rendered anemic by phenylhydrazine (PH) which was injected subcutaneously on alternate days as before. However, the hematocrit of each animal was determined at least every other day and the dose of PH, initially in the range of 16 mg/kg bodyweight, was adjusted as the anemia progressed so as to lower the hematocrit steadily to the desired level. In this way each animal was, in effect, “titrated” to a severe state of anemia. Once the hematocrit fell below lo%, the animal was exsanguinated. Our early results with normal sheep treated in this manner were erratic. Many of the animals died abruptly before becoming anemic, as was observed previously by White et a2.I Since the deaths were frequently associated with gastric and intestinal parasite infections, we turned to animals from a specific pathogen-free (SPF) flock which was free of parasites. With these animals we had no unexpected deaths and all animals had profound anemia when bled out. A further modification in our preparation of anemic sheep was prompted by recent experiments on the production of erythropoietin by rats. Hogson2 has found that total body radiation, which inhibited the erythropoietic response, facilitated the preparation of highly anemic animals and thus increased the yield of plasma erythropoietin. For our experiments, therefore, sheep were irradiated with 800 rads 6oCo y-rays (midline air dose given bilaterally at a dose rate of 15 rads/min. A further increase in the yield of plasma was achieved by infusing Ringer’s-Lactate solution during the bleed-out so as to flush the residual blood from the animal. Each animal was bled out from the carotid artery under local anesthesia and it was a simple matter at this time to infuse 1-2 of Ringer’s-Lactate solution into the jugular vein before the animal expired. The result of the modified procedure was a significant increase in yield of erythropoietin per sheep. The values of hematocrits for two typical SPF sheep treated as described above are shown in FIGURE 1. These animals were bled out at seven and nine days when their hematocrits had reached 8%. Each animal yielded about 10,000 units. TABLE 1 gives the yield of erythropoietin in the plasma of

The commercial production of erythropoietin from anemic sheep plasma

On the mechanism of erythropoietin-induced differentiation. 8. The effect of iron on stimulated marrow cell functions.

The enzymatic synthesis of 5-ribosyluridylic acid.

The organizers of this meeting, in celebration of the 20th anniversay of the operational definition of the pluripotent hemopoietic stem cell (CFU-S), have generously offered those of US who are chairing sessions, but not on the program, the opportunity of contributing a paper to the proceedings on the work of our laboratories. I would like to offer this short essay on one aspect of our research, in tribute to the “founding fathers,” even though they will probably not agree with our interpretation. I assume, in this discussion, that there exist substances analogous to erythropoietin (epo) that have similar roles as primary inducers of granulopoiesis (granulopoietin, gpo) and of megakaryopoiesis (megakaryopoietin, mkpo). Additionally, for the purpose of this paper, the following definitions are used:

Some thoughts on the nature of erythropoietin‐responsive cells

The erythroleukemic cell line IW32 has a normal erythropoietin (epo) gene and one which has undergone rearrangement and amplification. The rearranged epo locus consists of a breakpoint app...

Activation of the erythropoietin gene due to the proximity of an expressed gene.

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