A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia

Oscar A Campos; Narsis Attar; Chen Cheng; Maria Vogelauer; Nathan V Mallipeddi; Stefan Schmollinger; Nedas Matulionis; Heather R Christofk; Sabeeha S Merchant; Siavash K Kurdistani

doi:10.1126/sciadv.abj9889

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia

Sci Adv. 2021 Dec 17;7(51):eabj9889. doi: 10.1126/sciadv.abj9889. Epub 2021 Dec 17.

Authors

Oscar A Campos^{1

2}, Narsis Attar^{1

2}, Chen Cheng¹, Maria Vogelauer¹, Nathan V Mallipeddi¹, Stefan Schmollinger³, Nedas Matulionis¹, Heather R Christofk^{1

2

4}, Sabeeha S Merchant^{3

5

6}, Siavash K Kurdistani^{1

2

4}

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ QB3-Berkeley, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Departments of Molecular and Cell Biology and Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Abstract

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. A source of damage to Fe-S clusters is cuprous (Cu¹⁺) ions. Since histone H3 enzymatically produces Cu¹⁺ for copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3–mediated Cu¹⁺ toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply, due to diminished assembly as occurs in Friedreich’s ataxia or defective distribution, causes severe metabolic and growth defects in Saccharomyces cerevisiae. Decreasing Cu¹⁺ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster–dependent metabolism and growth. Our findings reveal an interplay between chromatin and mitochondria in Fe-S cluster homeostasis and a potential pathogenic role for histone enzyme activity and Cu¹⁺ in diseases with Fe-S cluster dysfunction.

Abstract

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