Abstract
Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include glutamate-cysteine ligase modifier subunit (Gclm), solute carrier family 7 member 11 (Slc7a11), ferritin heavy chain 1 (Fth1), ferritin light chain 1 (Ftl1), and solute carrier family 40 member 1 (Slc40a1). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that Bach1-/- mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.
Highlights
Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated
We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes
The amount of BACH1 protein was decreased in mouse embryonic fibroblasts (MEFs) exposed to erastin, which was accompanied by the induction of Hmox1 (Fig. 1, B and C, and Fig. S1)
Summary
Regulatory genes of ferroptosis show compensatory up-regulation in ferroptotic cells. Genes related to oxidative stress and iron metabolism showed significant induction in their expression (Fig. 1A) Many of these genes, for example, Slc7a11, Gclm, Gclc, are considered to possess inhibitory effects on ferroptosis [25]. Mitochondrial spheroids were not clear in Bach1Ϫ/Ϫ MEFs exposed to erastin, condensed matrix structures, which are observed as parts of mitochondrial spheroids [33], were observed (Fig. 2C) These results may reflect lower oxidative stress and higher resistance to erastin of Bach1Ϫ/Ϫ MEFs than WT MEFs. The cell death in our experiments was inhibited by the iron chelator deferoxamine (DFO) (Fig. 2, D and E), confirming that this death was ferroptosis. The amounts of SLC7A11 protein were similar in WT and Bach1Ϫ/Ϫ MEFs (Fig. 3, D and E, and Fig. S4, A and B), more SLC7A11 protein was present in Bach1Ϫ/Ϫ MEFs than in WT cells when they were treated with proteasome inhibitor MG132 (Fig. 3, D and E)
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