title: Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.
abstract: Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease caused by mutations in APTX, which encodes the DNA strand-break repair protein aprataxin (APTX). CoQ10 deficiency has been identified in fibroblasts and muscle of AOA1 patients carrying the common W279X mutation, and aprataxin has been localized to mitochondria in neuroblastoma cells, where it enhances preservation of mitochondrial function. In this study, we show that aprataxin deficiency impairs mitochondrial function, independent of its role in mitochondrial DNA repair. The bioenergetics defect in AOA1-mutant fibroblasts and APTX-depleted Hela cells is caused by decreased expression of SDHA and genes encoding CoQ biosynthetic enzymes, in association with reductions of APE1, NRF1 and NRF2. The biochemical and molecular abnormalities in APTX-depleted cells are recapitulated by knockdown of APE1 in Hela cells and are rescued by overexpression of NRF1/2. Importantly, pharmacological upregulation of NRF1 alone by 5-aminoimidazone-4-carboxamide ribonucleotide does not rescue the phenotype, which, in contrast, is reversed by the upregulation of NRF2 by rosiglitazone. Accordingly, we propose that the lack of aprataxin causes reduction of the pathway APE1/NRF1/NRF2 and their target genes. Our findings demonstrate a critical role of APTX in transcription regulation of mitochondrial function and the pathogenesis of AOA1 via a novel pathomechanistic pathway, which may be relevant to other neurodegenerative diseases.
authors.affiliation: Department of Neurology.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcia-Diaz
authors.affiliation: Department of Neurology, UOC of Neurology and Neuromuscular Disorders, Department of Neuroscience, University of Messina, Messina 98100, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Barca
authors.affiliation: Department of Neurology.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balreira
authors.affiliation: Department of Neurology, Institute of Biotechnology, Biomedical Research Center (CIBM), Health Science Technological Park (PTS), University of Granada, Armilla, Granada 18100, Spain and.
authors.forename: Luis C
authors.initials: LC
authors.lastname: Lopez
authors.affiliation: Department of Neurology.
authors.forename: Saba
authors.initials: S
authors.lastname: Tadesse
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Naini
authors.affiliation: Unitâ di Genetica delle Malattie Neurodegenerative e Metaboliche, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan 20126, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.affiliation: Unitâ di Genetica delle Malattie Neurodegenerative e Metaboliche, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan 20126, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castellotti
authors.affiliation: Department of Neurology, cmq2101@cumc.columbia.edu.
authors.forename: Catarina M
authors.initials: CM
authors.lastname: Quinzii
mesh_terms: D001259:Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495633:NRF1 protein, human; D009687:Nuclear Proteins; D051266:Nuclear Respiratory Factor 1; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase