Homoeostasis and distribution of essential metals in cells: Principles and molecular mechanisms

It has long been recognized that all organisms have a requirement for a range of metal ions, serving a variety of purposes (Table 1)1. The consequences of deficiency for each of these metal ions are grave; however, even essential metal ions are demonstrably toxic at elevated concentrations2. Therefore both unicellular and multicellular organisms have developed sophisticated mechanisms to regulate the intracellular concentrations and distribution of essential metal ions. The importance of such mechanisms is illustrated by the severity of genetic diseases related to metal mishandling, which include thalassaemias (iron overload), pernicious anaemia (diminished cobalt absorption), Wilson's and Menkes' diseases (copper mis-distribution), and acrodermatitis enteropathica (congenital zinc deficiency)3, with several of these diseases being fatal if untreated. It is also thought that impaired metal ion homoeostasis is a hallmark of aging4, and several neurodegenerative diseases including Alzheimer's and Parkinson's diseases are also intimately linked to misbalanced metal distribution5.