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

被引:11
作者
Davide, Doni [1 ]
Federica, Cavion [1 ]
Marco, Bortolus [2 ]
Elisa, Baschiera [3 ,4 ]
Silvia, Muccioli [1 ]
Giulia, Tombesi [1 ]
Federica, d'Ettorre [1 ]
Ottaviani, Daniele [1 ]
Elena, Marchesan [1 ]
Luigi, Leanza [1 ]
Elisa, Greggio [1 ,5 ]
Elena, Ziviani [1 ]
Antonella, Russo [6 ]
Milena, Bellin [1 ,7 ,8 ]
Geppo, Sartori [9 ]
Donatella, Carbonera [2 ]
Leonardo, Salviati [3 ,4 ]
Paola, Costantini [1 ]
机构
[1] Univ Padua, Dept Biol, I-35121 Padua, Italy
[2] Univ Padua, Dept Chem Sci, I-35131 Padua, Italy
[3] Univ Padua, Dept Womens & Children Hlth, Clin Genet Unit, I-35128 Padua, Italy
[4] Ist Ric Pediat IRP Citta Speranza, I-35127 Padua, Italy
[5] Univ Padua, Ctr Studi Neurodegeneraz CESNE, Padua, Italy
[6] Univ Padua, Dept Mol Med, I-35121 Padua, Italy
[7] Veneto Inst Mol Med, I-35129 Padua, Italy
[8] Leiden Univ, Med Ctr, Dept Anat & Embryol, NL-2333 ZA Leiden, Netherlands
[9] Univ Padua, Dept Biomed Sci, Padua, Italy
关键词
IRON-BINDING PROPERTIES; CRYSTAL-STRUCTURE; SULFUR CLUSTERS; COMPLEX-I; CARDIOMYOPATHY; MOUSE; BIOGENESIS; SUPERCOMPLEXES; ABNORMALITIES; MUTATIONS;
D O I
10.1038/s41419-023-06320-y
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:14
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