Abstract
In response to Ravera et al. “Fanconi anemia: from DNA repair to metabolism” commenting on our recent publication by Abu-Libdeh, Douiev et al., describing a pathogenic variant in the COX 4I1 gene simulating Fanconi anemia, we wish to add supplementary, pertinent information linking cytochrome c oxidase (COX, mitochondrial respiratory chain complex IV) dysfunction to oxidative stress and nuclear DNA damage. Elevated production of reactive oxygen species (ROS) in COX 4I1 deficient fibroblasts was detected in cells grown in glucose free medium and normalized by ascorbate or N-acetylcysteine supplementation. A pilot study shows positive nuclear staining with antibodies against Phospho-Histone H2A.X (Ser 139) indicating double-stranded DNA breaks (DBSs) both in COX 4I1 and in COX6B1 deficient fibroblasts. Additional investigation is required, and ongoing, to elucidate the precise mechanism of DNA damage in mitochondrial respiratory chain dysfunction and how it could be prevented.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ravera S, Dufour C, Degan P, Cappelli E. Fanconi anemia: from DNA repair to metabolism [letter]. Eur J Hum Genet. 2018, this issue.
Abu-Libdeh B, Douiev L, Amro S, Shahrour M, Ta-Shma A, Miller C, et al. Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. Eur J Hum Genet. 2017;25:1142–46.
Bourens M, Fontanesi F, Soto IC, Liu J, Barrientos A. Redox and reactive oxygen species regulation of mitochondrial cytochrome C oxidase biogenesis. Antioxid Redox Signal. 2013;19:1940–52.
Rak M, Bénit P, Chrétien D, Bouchereau J, Schiff M, El-Khoury R, et al. Mitochondrial cytochrome c oxidase deficiency. Clin Sci (Lond). 2016;130:393–7.
Abdulhag UN, Soiferman D, Schueler-Furman O, et al. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. Eur J Hum Genet. 2015;23:159–64.
Golubitzky A, Dan P, Weissman S, Link G, Wikstrom JD, Saada A. Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE. 2011;6:e26883.
Douiev L, Soiferman D, Alban C, Saada A. The effects of ascorbate, N-acetylcysteine, and resveratrol on fibroblasts from patients with mitochondrial disorders. J Clin Med. 2016;6:pii: E1 https://doi.org/10.3390/jcm6010001.
Viscomi C, Bottani E, Civiletto G, Cerutti R, Moggio M, Fagiolari G, et al. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell Metab. 2011;14:80–90.
Liang DH, Choi DS, Ensor JE, Kaipparettu BA, Bass BL, Chang JC. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair. Cancer Lett. 2016;376:249–58.
Acknowledgements
A.S. is supported by the Pakula family via AFHU. Dr. Yael Feinstein-Rotkopf from the Core Research Facility, Hebrew University Faculty of Medicine, is acknowledged for expert assistance with confocal microscopy.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Douiev, L., Abu-Libdeh, B. & Saada, A. Cytochrome c oxidase deficiency, oxidative stress, possible antioxidant therapy and link to nuclear DNA damage. Eur J Hum Genet 26, 579–581 (2018). https://doi.org/10.1038/s41431-017-0047-5
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41431-017-0047-5
This article is cited by
-
Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes
Nature Communications (2025)
-
Dexmedetomidine attenuates postoperative spatial memory impairment after surgery by reducing cytochrome C
BMC Anesthesiology (2023)
-
Grape seed proanthocyanidins protect retinal ganglion cells by inhibiting oxidative stress and mitochondrial alteration
Archives of Pharmacal Research (2020)
-
Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from high glucose-induced apoptosis
Endocrine (2018)
