Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms

Iron is an essential micronutrient that is problematic for biological systems since it is toxic as it generates free radicals by interconverting between ferrous (Fe²⁺) and ferric (Fe³⁺) forms. Additionally, even though iron is abundant, it is largely insoluble so cells must treat biologically available iron as a valuable commodity. Thus elaborate mechanisms have evolved to absorb, re-cycle and store iron while minimizing toxicity. Focusing on rarely encountered situations, most of the existing literature suggests that iron toxicity is common. A more nuanced examination clearly demonstrates that existing regulatory processes are more than adequate to limit the toxicity of iron even in response to iron overload. Only under pathological or artificially harsh situations of exposure to excess iron does it become problematic. Here we review iron metabolism and its toxicity as well as the literature demonstrating that intracellular iron is not toxic but a stress responsive programmed cell death-inducing second messenger.