Iron toxicity and mitochondrial oxidative stress

Abstract

Manganese containing superoxide dismutase (SOD2) protects mitochondria from oxidative damage, and loss of SOD2 can lead to severe oxidative stress and lethality in various organisms. Enzyme catalysis is carried out by a manganese ion co-factor, and binding of other metals such as iron to the active site would block SOD2 activity. In mitochondria, iron levels are in vast excess over manganese, by nearly 2 orders of magnitude. And SOD2 is predicted to bind iron with the same affinity as manganese. Even so, SOD2 has been reported to bind only its cognate manganese co-factor in vivo. Using the bakers yeast as a model system, we have been probing this apparent exquisite selectivity for manganese over iron. During the course of these studies, we uncovered some surprising aberrations in SOD2 metallation. Specifically, mitochondrial iron overload syndromes can promote iron association with SOD2. Iron precludes manganese from binding to SOD2 in vivo and enzymatic activity is destroyed. Iron also binds to SOD2 when mitochondrial manganese levels are low, even in the absence of iron overload. Our studies have revealed the existence of at least two distinct pools of mitochondrial iron: a SOD2-inert pool that predominates under normal growth conditions and competes poorly with manganese; and a SOD2-reactive form of iron that can become prevalent during iron overload and competes very well with manganese for binding to SOD2. Mitochondrial iron overload has long been associated with oxidative damage, with the primary suspect being iron-catalyzed Fenton chemistry. However, our studies suggest another potentially damaging outcome of iron overload: loss of mitochondrial SOD2. A number of human disorders have been linked to mitochondrial iron overload, and loss of this important anti-oxidant enzyme is a factor worth considering.