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. 2022 Jan;289(2):374-385.
doi: 10.1111/febs.15842. Epub 2021 Apr 7.

Understanding the role of cysteine in ferroptosis: progress & paradoxes

Carson D Poltorack  1 , Scott J Dixon  1
Affiliations

Understanding the role of cysteine in ferroptosis: progress & paradoxes

Carson D Poltorack et al. FEBS J. 2022 Jan.

Abstract

Cysteine is a conditionally essential amino acid required for the synthesis of proteins and many important intracellular metabolites. Cysteine depletion can trigger iron-dependent nonapoptotic cell death-ferroptosis. Despite this, cysteine itself is normally maintained at relatively low levels within the cell, and many mechanisms that could act to buffer cysteine depletion do not appear to be especially effective or active, at least in cancer cells. How do we reconcile these seemingly paradoxical features? Here, we describe the regulation of cysteine and its contribution to ferroptosis and speculate about how the levels of this amino acid are controlled to govern nonapoptotic cell death.

Keywords: cysteine; ferroptosis; glutathione; iron; metabolism.

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Conflict of interest statement

Conflicts of interest: S.J.D. is a member of the scientific advisory board of Ferro Therapeutics, has consulted for AbbVie and Toray Industries, and holds patents related to ferroptosis.

Figures

Figure 1.
Figure 1.
Overview of major elements of the ferroptosis pathway, with emphasis on the role of cysteine. Specific connections are annotated in the context of the existing literature on cysteine and ferroptosis as high confidence or as having emerging evidence. Note: for simplicity, transport and enzymatic reactions are not depicted in full, and not all known regulatory connections impacting cysteine metabolism are indicated.
Figure 2.
Figure 2.
Structure of cysteine-containing metabolites. The disulfide or free thiol of each molecule is highlighted in red.
Figure 3.
Figure 3.
A timing-based model of how cysteine depletion impacts cell fate. Cell a (black line) experiences rapid cysteine depletion and undergoes ferroptosis, while cell b (green line) experiences slow cysteine depletion and is able to adapt via the upregulation of compensatory processes (e.g., ATF4 pathway activity).
See this image and copyright information in PMC

References

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