Structure, function, and assembly of heme centers in mitochondrial respiratory complexes

Abstract

The sequential flow of electrons in the respiratory chain, from a low reduction potential substrate to O2, is mediated by protein-bound redox cofactors. In mitochondria, hemes—together with flavin, iron–sulfur, and copper cofactors—mediate this multi-electron transfer. Hemes, in three different forms, are used as a protein-bound prosthetic group in succinate dehydrogenase (complex II), in bc1 complex (complex III) and in cytochrome c oxidase (complex IV). The exact function of heme b in complex II is still unclear, and lags behind in operational detail that is available for the hemes of complex III and IV. The two b hemes of complex III participate in the unique bifurcation of electron flow from the oxidation of ubiquinol, while heme c of the cytochrome c subunit, Cyt1, transfers these electrons to the peripheral cytochrome c. The unique heme a3, with CuB, form a catalytic site in complex IV that binds and reduces molecular oxygen. In addition to providing catalytic and electron transfer operations, hemes also serve a critical role in the assembly of these respiratory complexes, which is just beginning to be understood. In the absence of heme, the assembly of complex II is impaired, especially in mammalian cells. In complex III, a covalent attachment of the heme to apo-Cyt1 is a prerequisite for the complete assembly of bc1, whereas in complex IV, heme a is required for the proper folding of the Cox 1 subunit and subsequent assembly. In this review, we provide further details of the aforementioned processes with respect to the hemes of the mitochondrial respiratory complexes. This article is part of a Special Issue entitled: Cell Biology of Metals

The heme exporter Flvcr1 regulates expansion and differentiation of committed erythroid progenitors by controlling intracellular heme accumulation

“…In eukaryotic cells, heme is embedded in the proteins of the electron transport chain and it is sequentially reduced and oxidized to transfer electrons that ultimately reduce O 2 . 24 Thus, it is conceivable that cytosolic heme availability must be regulated to allow the electron transport chain function. We think that Flvcr1a contributes to maintain a pool of de novo synthesized heme required to sustain the activity of hemoproteins as previously demonstrated in hepatocytes.…”

The Assembly Factor Pet117 Couples Heme a Synthase Activity to Cytochrome Oxidase Assembly

“…Heme a delivery to maturing Cox1 also depends on two additional proteins, Shy1/SURF1 and Coa2 (3,7). The formation of the heme a and heme a 3 centers appears to occur within the Shy1-containing Cox1 assembly intermediate, and Shy1 appears to chaperone maturation of the heme a 3 site rather than serve as a direct heme a donor to newly synthesized Cox1 (12).…”

“…After its translation by a mitochondrial ribosome and insertion into the mitochondrial inner membrane (IM), Cox1 undergoes sequential maturation aided by multiple assembly factors and receives its cofactors (2,3,7). Before being joined by the other core CcO subunits, Cox1 can be found in at least three distinct assembly intermediate complexes, which can be identified by the characteristic presence of the assembly factors Mss51, Coa1, and Shy1, respectively (Fig.…”

“…One major route for newly synthesized heme is its modification to form heme a, which is uniquely used by cytochrome c oxidase (CcO 3 ; Complex IV), the heme-copper terminal enzyme of the mitochondrial electron transport chain (2,3). Two heme a molecules with different coordination geometries, an isolated heme a moiety and a heterobimetallic cofactor center designated the heme a 3 -Cu B site, reside in the core CcO subunit Cox1, where they are essential for the stability and folding of Cox1 as well as enzymatic activity (3,4).…”

“…One major route for newly synthesized heme is its modification to form heme a, which is uniquely used by cytochrome c oxidase (CcO 3 ; Complex IV), the heme-copper terminal enzyme of the mitochondrial electron transport chain (2,3). Two heme a molecules with different coordination geometries, an isolated heme a moiety and a heterobimetallic cofactor center designated the heme a 3 -Cu B site, reside in the core CcO subunit Cox1, where they are essential for the stability and folding of Cox1 as well as enzymatic activity (3,4). These heme a cofactors are derived from heme b by the sequential actions of the conserved enzymes heme o synthase (Cox10), which mediates farnesylation of a vinyl group to yield heme o intermediate, and heme a synthase (Cox15), which converts heme o to heme a through oxidation of a methyl group in a reaction dependent upon the ferredoxin-ferredoxin reductase relay (3,5,6).…”