How does superoxide dismutase protect against tumor necrosis factor: a hypothesis informed by effect of superoxide on "free" iron.

The manganese-containing mitochondrial superoxide dismutase (MnSOD) is induced by TNF and protects against the necrotic effect of this cytokine. Yet TNF does not increase production of O2- in mitochondria. How is this to be reconciled? TNF is known to increase production of arachidonate, by activation of phospholipase A2 (PLA2). Arachidonate will be converted to the corresponding alkyl hydroperoxide by lipoxygenase. O2- increases "free" iron by oxidizing [4Fe-4S] clusters of dehydratases, such as aconitase. Ferrous iron in turn reacts with alkyl hydroperoxides, in an analogue of the Fenton reaction, to produce alkoxyl radicals: which can initiate the oxidation of polyunsaturated lipids by a free radical chain reaction. MnSOD protects against TNF by decreasing O2- attack on [4Fe-4S] clusters and thus lowering free iron. Inhibitors of PLA2 and of lipoxygenase should also protect by decreasing fatty acyl hydroperoxides and they are known to do so. Cells having little mitochondrial MnSOD, or cells unable to induce that defensive enzyme in response to TNF, will consequently have relatively high levels of "free" iron in that organelle; leading to enhanced lipid peroxidation. Such cells will be preferentially killed by this cytokine.