Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway

• Published in: Human molecular genetics Vol. 24; no. 16; pp. 4516 - 4529
• Main Authors: Garcia-Diaz, Beatriz, Barca, Emanuele, Balreira, Andrea, Lopez, Luis C, Tadesse, Saba, Krishna, Sindhu, Naini, Ali, Mariotti, Caterina, Castellotti, Barbara, Quinzii, Catarina M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15-08-2015
• Subjects: Ataxia - genetics; Ataxia - metabolism; Ataxia - pathology; DNA-(Apurinic or Apyrimidinic Site) Lyase - biosynthesis; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Down-Regulation; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - metabolism; Genetic Diseases, Inborn - pathology; Humans; Male; Mitochondria - metabolism; Mitochondria - pathology; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Respiratory Factor 1 - biosynthesis; Nuclear Respiratory Factor 1 - genetics; Signal Transduction
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv183

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.