Abstract
Cellular iron homeostasis and mitochondrial iron homeostasis are interdependent. Mitochondria must import iron to form iron–sulfur clusters and heme, and to incorporate these cofactors along with iron ions into mitochondrial proteins that support essential functions, including cellular respiration. In turn, mitochondria supply the cell with heme and enable the biogenesis of cytosolic and nuclear proteins containing iron–sulfur clusters. Impairment in cellular or mitochondrial iron homeostasis is deleterious and can result in numerous human diseases. Due to its reactivity, iron is stored and trafficked through the body, intracellularly, and within mitochondria via carefully orchestrated processes. Here, we focus on describing the processes of and components involved in mitochondrial iron trafficking and storage, as well as mitochondrial iron–sulfur cluster biogenesis and heme biosynthesis. Recent findings and the most pressing topics for future research are highlighted.
Highlights
Most iron in vertebrates is used to make heme b cofactors for hemoglobin in red blood cells; the essential nature of iron derives from more than this role in oxygen transport through the bloodstream
Ferroptosis is primarily initiated by iron-dependent lipid peroxidation, which can be caused by aberrant mitochondrial iron storage, defective iron–sulfur clusters (ISCs) biogenesis, or disturbed heme homeostasis
Much is known about how iron is trafficked extracellularly, as well as cytosolically, and how it is delivered to various organelles, but there remain many gaps in the information known about mitochondrial iron transport and the movement of iron-containing cofactors
Summary
Most iron in vertebrates is used to make heme b cofactors for hemoglobin in red blood cells; the essential nature of iron derives from more than this role in oxygen transport through the bloodstream. To generate ATP, mitochondria—and, mitochondrial enzymes composing the citric acid cycle (TCA cycle) and oxidative phosphorylation system (OXPHOS)— require the iron-containing cofactors iron–sulfur clusters (ISCs) and heme [4,6,7,8]. These two types of cofactors are produced via highly conserved processes through multistep synthetic pathways that occur in part in the mitochondrial matrix [7,8]. Both ISC biogenesis and heme biosynthesis require proper iron homeostasis, which begins with environmental iron acquisition and its efficient translocation to the mitochondrial matrix
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