Edenharter, Oliver and Clement, Janik and Schneuwly, Stephan and Navarro, Juan A. (2017) Overexpression of Drosophila frataxin triggers cell death in an iron-dependent manner. JOURNAL OF NEUROGENETICS, 31 (4). pp. 189-202. ISSN 0167-7063, 1563-5260
Full text not available from this repository. (Request a copy)Abstract
Friedreich ataxia (FRDA) is the most important autosomal recessive ataxia in the Caucasian population. FRDA patients display severe neurological and cardiac symptoms that reflect a strong cellular and axonal degeneration. FRDA is caused by a loss of function of the mitochondrial protein frataxin which impairs the biosynthesis of iron-sulfur clusters and in turn the catalytic activity of several enzymes in the Krebs cycle and the respiratory chain leading to a diminished energy production. Although FRDA is due to frataxin depletion, overexpression might also be very helpful to better understand cellular functions of frataxin. In this work, we have increased frataxin expression in neurons to elucidate specific roles that frataxin might play in these tissues. Using molecular, biochemical, histological and behavioral methods, we report that frataxin overexpression is sufficient to increase oxidative phosphorylation, modify mitochondrial morphology, alter iron homeostasis and trigger oxidative stress-dependent cell death. Interestingly, genetic manipulation of mitochondrial iron metabolism by silencing mitoferrin successfully improves cell survival under oxidative-attack conditions, although enhancing antioxidant defenses or mitochondrial fusion failed to ameliorate frataxin overexpression phenotypes. This result suggests that cell degeneration is directly related to enhanced incorporation of iron into the mitochondria. Drosophila frataxin overexpression might also provide an alternative approach to identify processes that are important in FRDA such as changes in mitochondrial morphology and oxidative stress induced cell death.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FRIEDREICHS-ATAXIA; OXIDATIVE STRESS; PARKINSONS-DISEASE; LIFE-SPAN; MITOCHONDRIAL DYSFUNCTION; CLUSTER FORMATION; LIPID-METABOLISM; HDAC INHIBITORS; MODEL; DEFICIENCY; Drosophila melanogaster; frataxin; overexpression; neuronal death; oxidative stress; mitochondrial morphology; iron metabolism; mitoferrin |
| Subjects: | 500 Science > 590 Zoological sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Zoologie > Entwicklungsbiologie (Prof. Dr. Stephan Schneuwly) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 20 Feb 2019 14:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/594 |
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