Iron and Copper in Mitochondrial Diseases

Abstract

Summary Transition metals are frequently used as co-factors for enzymes and oxygen-carrying proteins that take advantage of their propensity to gain and lose single electrons. Metals are particularly important in mitochondria, where they play essential roles in the production of ATP and detoxification of reactive oxygen species. At the same time, transition metals (particularly Fe and Cu) can promote the formation of harmful radicals, necessitating meticulous control of metal concentration and subcellular compartmentalization. We summarize our current understanding of Fe and Cu in mammalian mitochondrial biology, and discuss human diseases associated with aberrations in mitochondrial metal homeostasis.

Thiol Redox Sensitivity of Two Key Enzymes of Heme Biosynthesis and Pentose Phosphate Pathways: Uroporphyrinogen Decarboxylase and Transketolase

“…Iron serves as a cofactor for a wide variety of cellular processes, including oxygen transport, cellular respiration, the tricarboxylic acid (TCA) cycle, lipid metabolism, synthesis of metabolic intermediates, gene regulation, and DNA replication and repair [7]. Complex biosynthetic pathways are used for the assembly of Fe-porphyrin (Heme) and Fe–S clusters, essential cofactors of a large number of important enzymes.…”

Mitochondria represent another locale for the divalent metal transporter 1 (DMT1)

“…Indeed, iron flux through the inner mitochondrial membrane is regulated through differential turnover of mitoferrins. 4 In contrast, until recently it has been assumed (despite the absence of any experimental evidence) that transport of essential metal ions, including iron, across the outer mitochondrial membrane should occur via free permeation of these metal ions through voltage-dependent anion-selective channels (VDACs), 5 with the na€ ıve notion that VDACs are large nonselective diffusion pores through which small hydrophilic solutes can freely diffuse (however see Colombini). 6 The divalent metal transporter 1 (DMT1) is well established as a participant in iron influx into the duodenum, as the major contributor to iron efflux from the endosome during the transferrin (Tf) cycle and in handling some Tf-independent entry of iron and other metals (including copper and manganese) into many cell types.…”

TMEM14C is required for erythroid mitochondrial heme metabolism

“…Because TMEM14C is a mitochondrial protein required for heme synthesis, we assayed for biomarkers reflective of iron homeostasis (39). Tmem14c deficiency did not alter basal cellular 55 Fe uptake, although the amount of 55 Fe uptake was decreased in differentiating Tmem14c-deficient cells ( Figure 5A).…”