Abstract
Regulation of body fluid homeostasis is a major renal function, occurring largely through epithelial solute transport in various nephron segments driven by Na+/K+-ATPase activity. Energy demands are greatest in the proximal tubule and thick ascending limb where mitochondrial ATP production occurs through oxidative phosphorylation. Mitochondria contain 20–80% of the cell’s iron, copper, and manganese that are imported for their redox properties, primarily for electron transport. Redox reactions, however, also lead to reactive, toxic compounds, hence careful control of redox-active metal import into mitochondria is necessary. Current dogma claims the outer mitochondrial membrane (OMM) is freely permeable to metal ions, while the inner mitochondrial membrane (IMM) is selectively permeable. Yet we recently showed iron and manganese import at the OMM involves divalent metal transporter 1 (DMT1), an H+-coupled metal ion transporter. Thus, iron import is not only regulated by IMM mitoferrins, but also depends on the OMM to intermembrane space H+ gradient. We discuss how these mitochondrial transport processes contribute to renal injury in systemic (e.g., hemochromatosis) and local (e.g., hemoglobinuria) iron overload. Furthermore, the environmental toxicant cadmium selectively damages kidney mitochondria by “ionic mimicry” utilizing iron and calcium transporters, such as OMM DMT1 or IMM calcium uniporter, and by disrupting the electron transport chain. Consequently, unraveling mitochondrial metal ion transport may help develop new strategies to prevent kidney injury induced by metals.
Highlights
Together with the lungs and intestines, the kidneys maintain mammalian body fluid homeostasis by excreting most metabolic end-products and controlling the concentration of most constituents
The inner mitochondrial membrane (IMM) with its increased surface area disrupts the outer mitochondrial membrane (OMM) culminating in the release of pro-apoptotic factors, like cytochrome c (cytC) or apoptosis inducing factor, from the IMS resulting in general mitochondrial
It is assumed that OMM permeability is solely governed by the existence of relatively large pores, partially represented by voltage dependent anion channel (VDAC) or porins, which constitute approximately 50% of OMM proteins, allowing unregulated passage of small solutes intended for the mitochondrial matrix
Summary
Mitochondria contain 20–80% of the cell’s iron, copper, and manganese that are imported for their redox properties, primarily for electron transport. We recently showed iron and manganese import at the OMM involves divalent metal transporter 1 (DMT1), an H+coupled metal ion transporter. Iron import is regulated by IMM mitoferrins, and depends on the OMM to intermembrane space H+ gradient. We discuss how these mitochondrial transport processes contribute to renal injury in systemic (e.g., hemochromatosis) and local (e.g., hemoglobinuria) iron overload. The environmental toxicant cadmium selectively damages kidney mitochondria by “ionic mimicry” utilizing iron and calcium transporters, such as OMM DMT1 or IMM calcium uniporter, and by disrupting the electron transport chain.
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