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Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

ABSTRACT: Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

PROVIDER: PRJNA772574 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16477900.fastq.gz	Fastqsanger.gz
	SRR16477901.fastq.gz	Fastqsanger.gz
	SRR16477881.fastq.gz	Fastqsanger.gz
	SRR16477882.fastq.gz	Fastqsanger.gz
	SRR16477883.fastq.gz	Fastqsanger.gz

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Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

2022-10-01 | GSE186088 | GEO

Computational design of potent and selective BAK and BAX binders

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Wild type mouse embryonic fibroblasts (MEF) vs Bax/BAK double knock out MEF treated with and without Nocodazole

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2023-06-12 | E-MTAB-10997 | biostudies-arrayexpress

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death.

Project description:Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.SignificanceIronomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.

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VDAC2 promotes BAX apoptotic activity

Project description:Intrinsic apoptosis is critical for normal physiology including the prevention of tumor formation. BAX and BAK, which are essential for mediating this process and for the cytotoxic action of many anti-cancer drugs, are thought to be regulated through similar mechanisms and act redundantly to drive apoptosis. Here we have established the various mitochondrial complexes that contain VDAC1, VDAC2, VDAC3 and BAX or BAK.

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