Oxidative stress and cell death: The role of iron

The partnership between iron and oxygen is indispensable to cell survival but turns into a life - threatening challenge if it becomes imbalanced. To safeguard proper iron handling, cellular iron management is based on the tight coupling of compartment – specific “labile” (i.e. redox – active) iron pools. In this machinery, the endo-/lysosomal pool of redox-active, labile iron plays a particularly critical role since it couples external and internal iron sources to metabolic iron needs, which involves hetero- and autophagic mechanisms such as the recently described ferritinophagy. Under pro-oxidant conditions, the continued requirement for iron is at the risk of an enhanced, Fenton–reaction based production of hydroxyl radicals which will initiate lipid peroxidation and thus promote the generation of reactive metabolites such as 4-hydroxynonenal (HNE). With respect to lysosomal integrity, HNE - protein adduct formation and enhanced aldehyde - driven protein crosslinking are of considerable relevance since both will hamper lysosome function and increase the risk of lysosomal membrane permeability (LMP). In turn, LMP can directly trigger the onset of an apoptotic or necrotic (lytic) mode of cell death. Hence, the lysosomal labile iron pool represents a critical determinant of lysosomal as well as cellular integrity, especially under conditions of oxidative stress. Based on these findings, a model of lysosomal metastability will be presented which links iron – derived lysosomal stress to cellular live / death decisions.