title: Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity.
abstract: Mitochondrial ferritin is a functional ferritin that localizes in the mitochondria. It is expressed in the testis, heart, brain, and cells with active respiratory activity. Its overexpression in cultured cells protected against oxidative damage and reduced cytosolic iron availability. However, no overt phenotype was described in mice with inactivation of the FtMt gene. Here, we used the doxorubicin model of cardiac injury in a novel strain of FtMt-null mice to investigate the antioxidant role of FtMt. These mice did not show any evident phenotype, but after acute treatment to doxorubicin, they showed enhanced mortality and altered heart morphology with fibril disorganization and severe mitochondrial damage. Signs of mitochondrial damage were present also in mock-treated FtMt(-/-) mice. The hearts of saline- and doxorubicin-treated FtMt(-/-) mice had higher thiobarbituric acid reactive substance levels, heme oxygenase 1 expression, and protein oxidation, but did not differ from FtMt(+/+) in the cardiac damage marker B-type natriuretic peptide (BNP), ATP levels, and apoptosis. However, the autophagy marker LC3 was activated. The results show that the absence of FtMt, which is highly expressed in the heart, increases the sensitivity of heart mitochondria to the toxicity of doxorubicin. This study represents the first in vivo evidence of the antioxidant role of FtMt.
  
  
  CONCLUSIONS
  Mitochondrial ferritin (FtMt) expressed in the heart has a protective antioxidant role. Acute treatment with doxorubicin caused the death of all FtMt(-/-) and only of 60 % FtMt(+/+) mice. The hearts of FtMt(-/-) mice showed fibril disorganization and mitochondrial damage. Markers of oxidative damage and autophagy were increased in FtMt(-/-) hearts. This is the first in vivo evidence of the antioxidant role of FtMt.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maccarinelli
authors.forename: Elena
authors.initials: E
authors.lastname: Gammella
authors.forename: Michela
authors.initials: M
authors.lastname: Asperti
authors.forename: Maria
authors.initials: M
authors.lastname: Regoni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Biasiotto
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.forename: Laura
authors.initials: L
authors.lastname: Cornaghi
authors.forename: Elena
authors.initials: E
authors.lastname: Donetti
authors.forename: Stefania
authors.initials: S
authors.lastname: Recalcati
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cairo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D066126:Cardiotoxicity; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D005293:Ferritins / Q000172:deficiency* / Q000235:genetics; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D000903:Antibiotics, Antineoplastic; D024101:Mitochondrial Proteins; D004317:Doxorubicin; D005293:Ferritins
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