Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain
Summary
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. © 2023. The Author(s).
| Authors | Doni D, Cavion F, Bortolus M, Baschiera E, Muccioli S, Tombesi G, d'Ettorre F, Ottaviani D, Marchesan E, Leanza L, Greggio E, Ziviani E, Russo A, Bellin M, Sartori G, Carbonera D, Salviati L, Costantini P |
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| Journal | Cell death & disease |
| Publication Date | 2023 Dec 8;14(12):805 |
| PubMed | 38062036 |
| PubMed Central | PMC10703789 |
| DOI | 10.1038/s41419-023-06320-y |