An extended network for regulation of heme homeostasis in cells

Iron-bound tetrapyrroles (hemes) are essential for regulating cellular functions and bioenergetics. The processes of heme biosynthesis, transport and degradation are responsible for the supply of heme in mitochondria and its insertion into other downstream proteins. What remains unresolved is how these processes interconnect, and the wider implications for the cell in the restoration of homeostasis when heme concentrations change. We demonstrate a wide-ranging and coordinated response to changes in intracellular heme in HEK293 cells, through a regulation machinery comprising a network of complementary mechanisms that extend well beyond the direct regulation of heme biosynthesis and degradation. These responses connect changes in heme homeostasis to mitochondrial function, including core metabolic processes such as the tricarboxylic acid cycle and oxidative phosphorylation, as well as to enzymes involved in the control and storage of iron. Our findings demonstrate far-reaching consequences to perturbations of heme homeostasis and provide insights into the complexity of the cellular hemome.