Gattermann Figure 5 (in Greenberg et al). Pathogenesis of mitochondrial iron overload as a consequence of respiratory chain dysfunction.

(A) Uncoupling protein-2, which is expressed during erythroid differentiation, diminishes the mitochondrial protein gradient. This stimulates the respiratory chain to run faster to restore the gradient. Accordingly, oxygen consumption is increased and a low-oxygen environment is created, which is needed to protect Fe²⁺ from reoxidation.

(B) A respiratory chain defect will slow down oxygen consumption and will thus leave more oxygen in the mitochondrial matrix. Therefore, some of the imported Fe²⁺ will become reoxidized. Fe³⁺ will be rejected by ferrochelatase and will thus accumulate in the mitochondrial matrix.