Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia

Abstract

SUMMARYFriedreich’s ataxia (FRDA) is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.

Iron Regulatory Protein 1 Sustains Mitochondrial Iron Loading and Function in Frataxin Deficiency

“…For that purpose, we crossed Fxn Alb mice with Irp1 KO animals. As observed previously (Martelli et al, 2012a), FXN ablation in the liver reduced life expectancy, with most Fxn Alb mice dying before 10 weeks of age ( Figure 2A). Surprisingly, IRP1 disruption exacerbated the impact of hepatic FXN deficiency, with no Irp1;Fxn Alb double KO animal surviving beyond 5 weeks of age (Irp1;Fxn Alb versus Fxn Alb ; p < 0.001) (Figure 2A).…”

“…Specific depletion of FXN in mouse liver (Fxn Alb mice) results in liver failure associated with mitochondrial dysfunction and premature death starting around 28 days of age (Martelli et al, 2012a). Further analysis of Fxn Alb livers showed early impairment of Fe-S-dependent activities such as total aconitases (ACO2 + IRP1), succinate dehydrogenase (SDH), ferrochelatase (FECH), and the DNA repair enzyme NTH1 at 14 days of age ( Figure 1A).…”

“…As liver failure in FXN deficiency is associated with mitochondrial dysfunction (Martelli et al, 2012a), we investigated the consequences of IRP1 deletion on hepatic mitochondria in Fxn Alb animals. Analysis by electron microscopy provided clear evidence that the overall mitochondrial morphology and ultrastructure was more affected in double Irp1;Fxn Alb than in single Fxn Alb mice ( Figure 3A).…”

“…Fxn Alb , Abcb7 Alb , Irp1, and Irp2 animals were obtained as described (Galy et al, 2005;Martelli et al, 2012a;Pondarré et al, 2006). Irp1 and Irp2 mice were crossed with Fxn Alb or Abcb7 Alb mice to generate double KO animals.…”

“…FRDA results from decreased expression of frataxin (FXN), a mitochondrial protein that regulates the early steps of Fe-S biogenesis through its interaction with the ISCU-NFS1-ISD11 complex Tsai and Barondeau, 2010). Characterization of conditional mouse models with FXN deletion in heart or liver demonstrated that FXN deficiency leads to primary Fe-S deficiency and mitochondrial dysfunction (Martelli et al, 2012a;Puccio et al, 2001).…”