Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples

Abstract

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

Fig. 1

The Haber-Weiss and Fenton reactions combine using poorly liganded iron in a catalytic cycle to produce the very damaging hydroxyl radical. Poorly liganded iron can also be liberated via the destruction of haem and other iron-containing substances. Peroxynitrite anion (ONOO⁻) is produced by the reaction of superoxide and nitric oxide (NO^•) which when protonated (pH ca 6.5–6.8) decomposes to OH^• and NO₂

Fig. 2

Some small molecules that are derived from the oxidative attack of hydroxyl and other radicals on cellular macromolecules and that can act as biomarkers of oxidative stress, including that mediated by iron

Fig. 3

Very strong relationship between serum ferritin concentrations and urinary concentrations of the DNA damage/oxidative stress marker 8-hydroxy-2′-deoxyguanosine. Data are replotted from Fig. 1 of Hori et al. (2010)

Fig. 4

A mind map (Buzan 2002) setting out the structure of this review. To read this start at “1 o’clock” and move outwards and clockwise

Fig. 5

Some of the interactions between the prion protein in its two main conformations, reactive oxygen species and iron dysregulation. This diagram is based on Fig. 12 of (Singh et al. 2010b), and illustrates in particular the autocatalytic nature of the ROS- and iron-dependent conversion of PrP^C to PrP^Sc and the neurotoxicity of the latter

Fig. 6

Iron catalyses the formation of the hydroxyl radical (and thence other kinds of ROS) that can react with proteins and lipids to denature them, leading to insoluble plaques and other fibrotic structures that can themselves bind/entrap the iron that caused their formation. This bound iron can cause further hydroxyl radical formation such that the process is autocatalytic. Eventually this overwhelms cellular defences, leading to cell death (with further release of iron)

Fig. 7

Large (17-fold) accumulation of EPR-detectable iron in atherosclerotic plaques relative to healthy non-atherosclerotic (‘intima’) controls. The difference is highly significant (P = 0.0001). Data are replotted from those in Fig. 1b of Stadler et al. (2004)

Fig. 8

The major events accompanying sepsis and the Systemic Inflammatory Response Syndrome. Note in particular the positive feedback by which the release of pro-inflammatory cytokines and ROSs leads to the release of poorly liganded iron (e.g. from ferritin and haem) that causes the release of further inflammatory cytokines and ROSs. In principle, iron chelators could interfere with this vicious cycle

Fig. 9

A diagram, based very loosely on the narrative in (Kohanski et al. 2007), illustrating how the autocatalytic activity of the reactions of superoxide, peroxide and the hydroxyl radical involving poorly liganded iron can exert a positive feedback leading to the death of cells

Fig. 10

‘Bow-tie’ models of cellular networks. There are many examples of cellular networks in which a large variety of possible initial events leads to complex sequelae, but these are mediated via a comparatively small number of ‘intermediate’ reactions. While in the present case it is suggested that these in part involve complex positive feedbacks, the general ‘bow-tie’ idea does allow one to recognise that despite the many different possible inputs, a broadly unitary kind of mechanism of action—here involving iron dysregulation—can reasonably be invoked to explain the multiple causes that can lead to cell death and destruction

Fig. 11

The three main iron chelators approved for clinical use

Fig. 12

The extent of cell damage caused by the unliganded iron-catalysed production of ROSs and RNSs is determined by many factors, some of which promote and some of which act against it. While the existence of hormesis (see text) means that the see-saw illustrated here is an imperfect metaphor, the diagram serves to illustrate the complexity of the problem and the need for a systems biology approach to its solution

Fig. 13

The steady-state concentrations of a molecule depend on the rates of production and removal of the molecule in question. Both lowering creation and increasing removal represents a particularly effective strategy relative to doing just one of these alone. Thus if C is the hydroxyl radical we can lower its concentration by decreasing A and/or B and by increasing the rates of the reaction to D and E. The latter (decrease of concentration of C) may sometimes better be effected by increasing the activities of enzymes yet further downstream

Fig. 14

The relationship between ‘forward’ and ‘inverse’ methods of systems biology. The comparison of two ‘inverse’ systems (one a control and one treated with a toxin) in terms of the estimation of which parameters have changed most allows one to infer the sites or modes of action of that toxin [In a related manner we also discriminate forward and reverse genetics, including chemical genetics (Kell 2006a, b)].