Metal acquisition and availability in the mitochondria.

Abstract

Diverse metal ions participate in multiple roles in protein structure and function. In addition to their role in catalysis, electron transfer, and ligand binding, metal ions are important for the structural integrity of many proteins. Physiological responses are known to ensure adequate cellular levels of essential metal ions, but less is known about both the process of protein metalation and metal ion availability within cellular compartments such as the mitochondrion. In general, metalation reactions are expected to occur during protein biosynthesis or shortly thereafter, since many metal cofactors are important determinants of protein stability. On cytoplasmic ribosomes, protein biosynthesis and chain elongation are coupled to chaperone-mediated protein folding for many proteins.1 Nascent polypeptides are protected within the ribosome and can only fold as they emerge from the exit tunnel. The molecular chaperones bind to nascent polypeptides and actively guide the polypeptides in folding through cycles of binding and release. Some proteins achieve a native conformer before final release from the ribosome.2,3 Metalloproteins are likely metalated at this stage. Biological metalation is dependent on both the availability of adequate bioavailable pools of metal ion and selectivity mechanisms to ensure metalation with the appropriate metal ion. Specific metalation is a significant issue, as proteins have only limited discrimination between binding various metal ions. Limited control over metalation is imposed by diverse preferences in coordination geometry and hardness/softness of ligand donor atoms between multiple metal ions. Moreover, for metal ions such as Zn(II), these imposed limits are more flexible. Zn(II) is able to coordinate with a variety of donor ligands due to its borderline hardness, and conversion between coordination numbers is possible due to a lack of any ligand field stabilization effects for Zn(II). These effects have the potential to raise both the difficulty in precise Zn site metalation and the misincorporation of Zn into other metalloproteins. Metalloproteins are compartmentalized within cells. Metalation of metalloproteins within mitochondria is expected to occur after protein import into the organelle. The vast majority of mitochondrial proteins, if not all, are imported as unfolded proteins, and folding occurs within the organelle. Iron, zinc, copper, and manganese ions are cofactors in metalloenzymes and metalloproteins within mitochondria. Thus, bioavailable pools of these metal ions must exist within the mitochondria for efficient metalation reactions. In this review, we will discuss the various paradigms that ensure specificity in metalation reactions during metalloprotein biosynthesis and the available literature on bioavailable metal ion pools in cells, with particular focus on the mitochondrial organelle. Perturbation of metal pools through disease or environmental factors can lead to detrimental mismetalation, underlining the importance of maintaining metal specificity. Thus, regulation of both metalation specificity and metal ion accessibility must exist.