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Iron Sulfur Clusters and ROS in Cancer

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Handbook of Oxidative Stress in Cancer: Mechanistic Aspects

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Abstract

Iron sulfur proteins (Fe-S) are ancient structures present in archaebacteria and are involved in central metabolic functions in these ancient organisms (Iwasaki, Archaea 2010:1, 2010). From an evolutionary perspective, Fe-S clusters originated early on during protein evolution; with the aid of an inducible and robust antioxidant defense system, organisms have evolved to tackle oxygen toxicity and metabolism. Since Fe-S cluster proteins are known to be responsible for a variety of physiological functions in mammals, destabilization of the clusters by oxidative and nitrosative stress can lead to consequences such as TCA cycle downregulation, mitochondrial dysfunction and also oxidative stress-induced carcinogenesis. Indeed, mutations of some Fe-S proteins have been correlated with cancer. Particularly, cancer pathophysiology has been linked to oxidative stress. Also, defective Fe-S cluster assembly due to genetic abnormalities is the underlying cause for several other diseases, which are discussed in detail in Roland Lill and Tracey Rouault’s works (Sheftel et al. Trends Endocrinol Metab 21 (5):302–314, 2010; Rouault and Tong, Trends Genet 24 (8):398–407, 2008; Ye and Rouault, Biochemistry 49 (24):4945–4956, 2010; Lill and Mühlenhoff, Annu Rev Biochem 77:669–700, 2008). Lack of mature Fe-S clusters in respiratory complexes leads to low energy (fatigue) and metabolic dysfunction because lipoic acid synthesis and many metabolic pathways are regulated by Fe-S proteins. Also, Fe-S cluster depletion in nuclear Fe-S proteins which are involved in DNA synthesis, maintenance and repair can potentially spark carcinogenesis. Moreover, since Fe-S cluster proteins are powerful ‘sensors’ of oxidative stress, they are important signalling agents which can alert cells to oxidative stress damage, and hence, were termed as “sentinels” (Py et al. Curr Opin Microbiol 14 (2):218–223, 2011). Reaction of Fe-S clusters with reactive oxygen and nitrogen species is an inevitable consequence of oxygen-dependent respiration; hence, cells possess machinery to synthesize and repair damaged Fe-S clusters, to restore protein functionality and cellular viability. When the oxidative damage overwhelms the antioxidant defense system and impairs Fe-S repair/reconstitution, there can be dire consequences, including cancer.

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Abbreviations

ATP:

Adenosine triphosphate

BOLA1:

BolA Family Member 1

CDGSH:

CDGSH iron sulfur domain 1 (MitoNEET)

CIA:

Cytosolic iron-sulfur protein assembly

DCA:

Dichloroacetate

DNIC:

Dinitrosyl-Iron Complex

DPYD:

Dihydropyrimidine Dehydrogenase

ELP3:

Elongator complex protein 3

EPR:

Electron paramagnetic resonance

ETC:

Electron transport chain

ETFDH:

Electron Transfer Flavoprotein Dehydrogenase

FADH:

Flavin adenine dinucleotide, reduced

FANCJ:

Fanconi anemia group J

FMN:

Flavin mononucleotide

FXN:

Frataxin

GLRX5:

Glutaredoxin 5

GPAT:

Glycerol-3-phosphate acyltransferase

IRE-BP:

Iron-responsive element-binding protein

IRP-1:

Iron regulatory protein

ISCU:

Iron-Sulfur Cluster Assembly Enzyme

MOCS1:

Molybdenum Cofactor Synthesis 1

MUTYH:

mutY DNA glycosylase

NADH:

Nicotinamide adenine dinucleotide

NAF-1:

Nuclear Assembly Factor 1

NDUFS:

NADH:Ubiquinone Oxidoreductase Core Subunit S

NFS1:

Cysteine desulfurase

NMR:

Nuclear Magnetic Resonance

NTHL1:

Nth Like DNA Glycosylase 1

PEITC:

β-Phenethyl isothiocyanate

RNS:

Reactive Nitrogen Species

ROS/RNS:

Reactive Oxygen species

SDHB:

Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial

TCA:

Tricarboxylic acid cycle

VDAC:

Voltage-dependent anion channels

XDH:

Xanthine dehydrogenase

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Author notes

  1. Joel James and Daniel Andrew M. Gideon has equally contributed to this chapter.

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, University of Arizona College of Medicine, Tucson, AZ, USA

    Joel James

  2. Department of Biotechnology and Bioinformatics, Bishop Heber College (Autonomous), Tiruchirappalli, Tamil Nadu, India

    Daniel Andrew M. Gideon

  3. Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Debasish Roy

  4. Department of Physiology, University of Arizona, Tucson, AZ, USA

    Amritlal Mandal

Authors
  1. Joel James
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  2. Daniel Andrew M. Gideon
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  3. Debasish Roy
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  4. Amritlal Mandal
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Corresponding author

Correspondence to Joel James .

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Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA

    Bimal K. Ray

  3. CSIR-Indian Institute of Chemical Biology, Kolkata, India

    Susanta Roychoudhury

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James, J., Gideon, D.A.M., Roy, D., Mandal, A. (2022). Iron Sulfur Clusters and ROS in Cancer. In: Chakraborti, S., Ray, B.K., Roychoudhury, S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-9411-3_24

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