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The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis

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Ferroptosis: Mechanism and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1301))

Abstract

Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin, the cytosolic iron storage complex, in a process known as ferritinophagy. NCOA4-mediated ferritinophagy is required to maintain intracellular and systemic iron homeostasis and thereby iron-dependent physiologic processes such as erythropoiesis. Given this role of ferritinophagy in regulating iron homeostasis, modulating NCOA4-mediated ferritinophagic flux alters sensitivity to ferroptosis, a non-apoptotic iron-dependent form of cell death triggered by peroxidation of polyunsaturated fatty acids (PUFAs). A role for ferroptosis has been established in the pathophysiology of cancer and neurodegeneration; however, the importance of ferritinophagy in these pathologies remains largely unknown. Here, we review the available evidence on biochemical regulation of NCOA4-mediated ferritinophagy and its role in modulating sensitivity to innate and induced ferroptosis in neurodegenerative diseases and cancer. Finally, we evaluate the potential of modulating ferritinophagy in combination with ferroptosis inducers as a therapeutic strategy.

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Abbreviations

4-HNE:

4-Hydroxynonenal

AD:

Alzheimer’s Disease

AP-MS:

Affinity-Purification Mass Spectrometry

ATG8:

Autophagy-Related Protein 8

BSO:

Buthionine Sulfoximine

COPD:

Chronic Obstructive Pulmonary Disease

DFO :

Deferoxamine

DMT1:

Divalent Metal Transporter 1

DNA:

Deoxyribonucleic Acid

ESCRT:

Endosomal Sorting Complex Required for Transport

Fe:

Iron

FPN:

Ferroportin

FTH1:

Ferritin Heavy Chain

FTL:

Ferritin Light Chain

GPX4 :

Glutathione Peroxidase 4

GSH :

Glutathione

H2O2:

Hydrogen Peroxide

HD:

Huntington’s Disease

HERC2:

HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2

HSCs:

Hepatic Stellate Cells

IREB2:

Iron Response Element Binding Protein 2

LA:

α-Lipoic acid

LIP:

Labile Iron Pool

LOX:

Lipoxygenase

MCAO :

Middle Cerebral Artery Occlusion

MEFs:

Mouse Embryonic Fibroblasts

NCOA4:

Nuclear Receptor Co-Activator 4

NEURL4 :

Neuralized E3 Ubiquitin Protein Ligase 4

NF:

Neuroferritinopathy

PD:

Parkinson’s Disease

PUFA:

Polyunsaturated Fatty Acid

ROS :

Reactive Oxygen Species

RSL3 :

RAS-Selective Lethal 3

SILAC:

Stable Isotopic Labeling with Amino Acids in Cell Culture

SLC7A11:

Solute Carrier Family 7 Member 11

TF:

Transferrin

TFRC:

Transferrin Receptor

xCT:

Cystine/Glutamate Transporter

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Acknowledgements

This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK124384, a Burroughs Wellcome Fund Career Award for Medical Scientists, and a Brigham and Women’s Hospital MFCD Award to J.D.M. Portions of the illustration were generated using Biorender.

Conflicts of Interest

J.D.M. is an inventor on a patent pertaining to the autophagic control of iron metabolism.

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Author notes

  1. Authors Naiara Santana-Codina, Ajami Gikandi, and Joseph D. Mancias have equally contributed to this chapter.

Authors and Affiliations

  1. Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Naiara Santana-Codina, Ajami Gikandi & Joseph D. Mancias

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  1. Naiara Santana-Codina
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  2. Ajami Gikandi
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Correspondence to Joseph D. Mancias .

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  1. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

    Andrés F. Florez

  2. Division of Stem Cells and Cancer German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany

    Hamed Alborzinia

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Santana-Codina, N., Gikandi, A., Mancias, J.D. (2021). The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis. In: Florez, A.F., Alborzinia, H. (eds) Ferroptosis: Mechanism and Diseases. Advances in Experimental Medicine and Biology, vol 1301. Springer, Cham. https://doi.org/10.1007/978-3-030-62026-4_4

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