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

ABSTRACT: Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support 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, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. 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 a novel 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.

ORGANISM(S): Yeast Saccharomyces Cerevisiae

TISSUE(S): Yeast Cells

DISEASE(S): Friedreichs Ataxia

SUBMITTER: Nedas Matulionis

PROVIDER: ST001954 | MetabolomicsWorkbench | Thu Oct 21 00:00:00 BST 2021

REPOSITORIES: MetabolomicsWorkbench

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

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