Determination of the Subcellular Localization and Mechanism of Action of Ferrostatins in Suppressing Ferroptosis

MichaelM. Gaschler, Fanghao Hu, Huizhong Feng, Andreas Linkermann, Wei Min, Brent R. Stockwell

Index: 10.1021/acschembio.8b00199

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Abstract

Ferroptosis is a form of nonapoptotic cell death characterized by the unchecked accumulation of lipid peroxides. Ferrostatin-1 and its analogs (ferrostatins) specifically prevent ferroptosis in multiple contexts, but many aspects of their molecular mechanism of action remain poorly described. Here, we employed stimulated Raman scattering (SRS) microscopy coupled with small vibrational tags to image the distribution of ferrostatins in cells and found that they accumulate in lysosomes, mitochondria, and the endoplasmic reticulum. We then evaluated the functional relevance of lysosomes and mitochondria to ferroptosis suppression by ferrostatins and found that neither is required for effective ferroptosis suppression.