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

2021 ◽  
Author(s):  
Oscar A Campos ◽  
Narsis Attar ◽  
Nathan V Mallipeddi ◽  
Chen Cheng ◽  
Maria Vogelauer ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Human Disease ◽  
Reductase Activity ◽  
Histone H3 ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Pathogenic Role ◽  
Growth Defects ◽  
Iron Sulfur ◽  
Cellular Copper

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 Fe-S cluster quotient. 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.

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

2021 ◽  
Vol 7 (51) ◽  
Author(s):  
Oscar A. Campos ◽  
Narsis Attar ◽  
Chen Cheng ◽  
Maria Vogelauer ◽  
Nathan V. Mallipeddi ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Histone H3 ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Pathogenic Role ◽  
Yeast Model

Deciphering Mitochondrial Iron Metabolism Using a Knockout Mouse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1995-1995
Author(s):  
Michael Huang ◽  
Erika Becker ◽  
Megan Whitnall ◽  
Yohan Suryo Rahmanto ◽  
Prem Ponka ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Knockout Mouse ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Down Regulation ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract 1995 Poster Board I-1017 We utilized the muscle creatine kinase conditional frataxin knockout mouse to elucidate how frataxin-deficiency alters iron metabolism. This is of significance since frataxin-deficiency leads to the neuro- and cardio-degenerative disease, Friedreich's ataxia. Using cardiac tissues, we demonstrate that frataxin-deficiency leads to down-regulation of key molecules involved in three mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase, Nfs1); mitochondrial-iron storage (mitochondrial ferritin); and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase and ferrochelatase). This marked decrease in mitochondrial-iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excess mitochondrial-iron observed. Indeed, this effect is compounded by increased iron availability for mitochondrial uptake through: (1) transferrin receptor1 up-regulation that increases iron uptake from transferrin; (2) decreased ferroportin1 expression, limiting iron export; (3) increased expression of the heme catabolism enzyme, heme oxygenase1, and down-regulation of ferritin-H and —L, both of which likely lead to increased “free iron” for mitochondrial uptake; and (4) increased expression of the mammalian exocyst protein, Sec15l1, and the mitochondrial-iron importer, mitoferrin-2 (Mfrn2), that facilitate cellular iron uptake and mitochondrial-iron influx, respectively. This study enables construction of a model explaining the cytosolic iron-deficiency and mitochondrial-iron-loading in the absence of frataxin that is important for understanding the pathogenesis of Friedreich's ataxia. Disclosures: No relevant conflicts of interest to declare.

Normal fibroblast mitochondrial malic enzyme activity in Friedreich's ataxia

Neurology ◽  
1986 ◽  
Vol 36 (6) ◽  
pp. 869-869 ◽  
Author(s):  
R. J. Fernandez ◽  
F. Civantos ◽  
E. Tress ◽  
W. A. Maltese ◽  
D. C. De Vivo
Keyword(s):  
Enzyme Activity ◽  
Malic Enzyme ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Normal Fibroblast ◽  
Malic Enzyme Activity ◽  
Mitochondrial Malic Enzyme

scholarly journals Leukocyte Valine Dehydrogenase Activity in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 235-238 ◽  
Author(s):  
A. Barbeau ◽  
T. Cloutier ◽  
M. Charbonneau
Keyword(s):  
Enzyme Activity ◽  
Dehydrogenase Activity ◽  
Normal Control ◽  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Control Subjects ◽  
Keto Acids

SUMMARY:We studied the activity of valine dehydrogenase (VDH) in leukocytes of 14 Friedreich’s ataxia patients and of 14 normal control subjects. There was a significant 26% mean decrease in enzyme activity in the patients, a finding which could be responsible for the chronic accumulation of some α-keto acids with toxic metabolic consequences in that disease. However the deficiency was not present in all patients with the typical symptoms, nor was its magnitude sufficient to be considered the primary genetic defect in Friedreich’s A taxia.

Otoneurological Findings in Friedreich's Ataxia and Other Inherited Neuropathies

1986 ◽  
Vol 25 (2) ◽  
pp. 84-91 ◽  
Author(s):  
E. Cassandro ◽  
F. Mosca ◽  
L. Sequino ◽  
F. A. De Falco ◽  
G. Campanella
Keyword(s):  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Inherited Neuropathies
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