Transition metals and mitochondrial metabolism in the heart

Abstract

Transition metals are essential to many biological processes in almost all organisms from bacteria to humans. Their versatility, which arises from an ability to undergo reduction-oxidation chemistry, enables them to act as critical cofactors of enzymes throughout the cell. Accumulation of metals, however, can also lead to oxidative stress and cellular damage. The importance of metals to both enzymatic reactions and oxidative stress makes them key players in mitochondria. Mitochondria are the primary energy-generating organelles of the cell that produce ATP through a chain of enzymatic complexes that require transition metals, and are highly sensitive to oxidative damage. Moreover, the heart is one of the most mitochondrially-rich tissues in the body, making metals of particular importance to cardiac function. In this review, we focus on the current knowledge about the role of transition metals (specifically iron, copper, and manganese) in mitochondrial metabolism in the heart. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Fig. 1

Systemic iron transport. Ferric iron (Fe^{3 +}) from the diet is converted to ferrous iron (Fe^{2 +}) in the duodenum by ferric reductases, then imported into enterocytes by DMT1. Heme from the diet is also imported into enterocytes and converted into ferrous iron by HO1. Ferrous iron is then exported into the bloodstream by Fpn. The export of ferrous iron is coupled to its conversion to ferric iron, which is catalyzed by hephaestin and ceruloplasmin. Iron export by Fpn can also be inhibited by the peptide hepcidin. In the bloodstream, ferric iron binds to transferrin, which enables import into target cells by binding to TfR. Ferric iron-bound TfR is then imported into cells by clathrin-coated pits. DMT1: Divalent metal transporter 1. Fpn: Ferroportin. Hp: Hephaestin. Ce: Ceruloplasmin. Tf: Transferrin. TfR: Transferrin receptor.

Fig. 2

Iron signaling in the mitochondria. The mechanism of iron import into the outer mitochondrial membrane is not fully known, but iron is imported into the inner mitochondrial membrane by Mfrn1 (assisted by ABCB10) and Mfrn2. The mechanism of iron export from the mitochondria is also not known, but is facilitated by the inner mitochondrial membrane protein ABCB8. In the mitochondria, iron remains as a labile iron pool, is bound by ferritin and stored, or is incorporated into ISC- and heme-containing enzymes of mitochondrial complexes of the electron transport chain. ISC and heme are also exported from the mitochondria by an unknown mechanism, then incorporated into non-mitochondrial ISC- and heme-containing enzymes. Mitochondrial complexes I and III produce superoxide ROS by electron leakage to O₂. This superoxide is protonated to form H₂O₂, which can then react with free iron to form hydroxyl radical ROS. CI–CIV: complexes I through IV. ISC: iron/sulfur cluster.

Fig. 3

Systemic and mitochondrial copper transport. Copper from the diet is imported into enterocytes by Ctr1, then exported into the bloodstream by ATP7A. In the bloodstream, the majority of copper is bound to ceruloplasmin. Copper is transported into cells by Ctr1, and across the outer mitochondrial membrane by an unknown mechanism. In the inter-membrane space, copper is bound by Cox17, which delivers copper to Sco1 or Cox11. Sco1-bound copper is delivered to the Cox1 subunit of Cco. Cox11-bound copper is delivered to the Cox2 subunit of Cco. Cu: Copper. Ce: Ceruloplasmin. OM: outer mitochondrial membrane. IS: intermembrane space. IM: inner mitochondrial membrane. Cco: cytochrome oxidase.