Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain

Abstract

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease caused by an expanded GAA repeat in the first intron of the FXN gene, leading to transcriptional silencing and reduced expression of frataxin. Frataxin participates in the mitochondrial assembly of FeS clusters, redox cofactors of the respiratory complexes I, II and III. To date it is still unclear how frataxin deficiency culminates in the decrease of bioenergetics efficiency in FRDA patients’ cells. We previously demonstrated that in healthy cells frataxin is closely attached to the mitochondrial cristae, which contain both the FeS cluster assembly machinery and the respiratory chain complexes, whereas in FRDA patients’ cells with impaired respiration the residual frataxin is largely displaced in the matrix. To gain novel insights into the function of frataxin in the mitochondrial pathophysiology, and in the upstream metabolic defects leading to FRDA disease onset and progression, here we explored the potential interaction of frataxin with the FeS cluster-containing respiratory complexes I, II and III. Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients’ cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient’s cells. Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for FRDA targeted to this respiratory complex.

Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I from Thermus thermophilus

“…The deficiency of FXN in human cells has been shown to mainly impact mitochondrial complex I [40], which, among the respiratory complexes, has a higher turnover rate and is particularly prone to intrinsic degradation and oxidative damage [57]. In this regard, it has been observed that the exogenous expression of recombinant Nqo15 in FRDA patients' cells is able to ameliorate the respiratory phenotype [40]; the extent of this effect is comparable to what is observed by re-expressing FXN in these cells, indirectly supporting the hypothesis that FXN could play a key role in mitochondrial complex I proteostasis.…”

“…We have recently shown that, in healthy human cells, FXN is associated with mitochondrial cristae, the subcompartment that houses the respiratory chain [39]. The raison d'être of this enrichment lies in the ability of FXN to functionally interact with respiratory complexes I, II and III, as demonstrated by combining different experimental approaches [40]. Remarkably, the decrease in FXN in FRDA cells has been shown to lead to the more severe impairment of complex I than complexes II and III, suggesting that FXN could have a specific role in the stabilization and/or functioning of the first complex of the respiratory chain.…”

“…However, although it shares the peculiar folding of FXN, Nqo15 shows a low degree of sequence identity, raising the question of whether the protein displays functional properties shared by all members of the FXN family, such as iron-binding and the enhancement of Fe-S cluster formation. Indeed, we have shown that the expression of a recombinant Nqo15 is capable of ameliorating the respiratory phenotype of FRDA patients' cells [40], and this prompted us to further characterize Nqo15.…”