Direct interorganellar transfer of iron from endosome to mitochondrion

Abstract

Iron is a transition metal whose physicochemical properties make it the focus of vital biologic processes in virtually all living organisms. Among numerous roles, iron is essential for oxygen transport, cellular respiration, and DNA synthesis. Paradoxically, the same characteristics that biochemistry exploits make iron a potentially lethal substance. In the presence of oxygen, ferrous iron (Fe 2؉ ) will catalyze the production of toxic hydroxyl radicals from hydrogen peroxide. In addition, Fe 3؉ is virtually insoluble at physiologic pH. To protect tissues from deleterious effects of Fe, mammalian physiology has evolved specialized mechanisms for extracellular, intercellular, and intracellular iron handling. Here we show that developing erythroid cells, which are taking up vast amounts of Fe, deliver the metal directly from transferrin-containing endosomes to mitochondria (the site of heme biosynthesis), bypassing the oxygen-rich cytosol. Besides describing a new means of intracellular transport, our finding is important for developing therapies for patients with iron loading disorders. IntroductionAlthough its requirement for life in almost all known organisms has been recognized for decades, some of the most fundamental cell biologic processes of iron (Fe) still elude modern science. Mammalian physiology demands a constant source of bioavailible Fe, which is a functional component of hemoproteins, iron-sulfur cluster containing proteins, and other iron proteins. However, in its reduced form (Fe 2ϩ ), iron catalyzes the production of toxic hydroxyl radicals through Fenton chemistry, while the ferric version (Fe 3ϩ ) is virtually insoluble at physiologic pH. [1][2][3] Nevertheless, the adult human body contains approximately 4 g of Fe, more than 80% of which is in hemoglobin (Hb). 4 Under normal conditions, around 2 million red blood cells (RBCs) are produced per second. Hence, erythropoiesis requires approximately 25 mg of iron, daily, all of which is delivered via transferrin (Tf). The plasma contains approximately 3 M diferric Tf, the Fe of which is concentrated in maturing erythroid tissue to the equivalent of 20 mM iron, in the form of Hb. This exceptionally rapid utilization of the potentially toxic metal requires stringent regulation mechanisms that permit efficient production of hemoglobin, while protecting developing red blood cells and other tissues from iron's harmful properties. 5 Virtually every tissue acquires its iron by receptor mediated endocytosis of Tf (for review, see Richardson and Ponka 6 and Hentze et al 7 ): Diferric Tf binds to its cognate receptor on the cell surface; this binding is succeeded by internalization of the receptorligand complex. The release of Fe from Tf is achieved within the endosome by a lowering of the vesicular pH through the activity of the v-ATPase proton pump. After its liberation from Tf in the acidified endosome, Fe must be reduced (possibly by the recently identified Steap3 8 ) before it is transported across the vesicular membrane by the divalent metal transp...

The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation

“…Although the unregulated disruption of the mitochondrial membrane is ordinarily implicated in cell death and apoptosis, there is increasing evidence that regulated vesicular transport may occur between mitochondria and other cellular organelles. For example, iron may be transported to the mitochondria via endosomes (32), and more recent studies have shown that membranous vesicles bud off from mitochondria, transporting fatty acids to the peroxisome (33). The data presented here suggest a role for mitochondria in the trafficking of ions or clusters of calcium and phosphate ions to the extracellular space, facilitating mammalian mineralization.…”

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

“…Further, it can be speculated that alterations in endosomal/organelle or Fechaperone trafficking may be involved in directing Fe targeting between the cytosol and mitochondrion. Direct endosomal and MIT contact to effect MIT Fe targeting may occur in erythroid cells (24,25). In addition, it is well known that organelle and transporter trafficking is involved in copper transport (26).…”

The role of lysosomes in iron metabolism and recycling

“…Whether or not iron in this pool is redox-active is unknown, neither is it known in which molecular form iron exists within this transient pool before it is incorporated and stored in ferritin or delivered to the mitochondria or elsewhere for synthesis of iron-sulfur complexes, heme and iron-containing enzymes. Recent studies on erythroid cells have given results that challenge the existence of a labile pool of iron in at least these particular cells and point to a docking process between late endosomes and mitochondria (Sheftel et al, 2007). Further research is needed to clarify the exact mechanisms of iron transport from late endosomes to ferritin or places of synthesis for ironcontaining macromolecules, mainly in the mitochondria.…”