期刊
CLINICAL SCIENCE
卷 130, 期 11, 页码 853-870出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20160072
关键词
frataxin; iron dys-regulation; mitochondrial iron processing; nuclear factor erythroid 2-related factor 2 (Nrf2); oxidative stress
资金
- National Health and Medical Research Council of Australia (NHMRC) [1062607]
- NHMRC Peter Doherty Early Career Fellowship [1074033]
- NHMRC R.D. Wright Career Development Fellowship [1083057]
- Sydney Medical School Foundation
- AMP Foundation Tomorrow Maker Award
- Sydney Medical School Early Career Researcher Grant
- CINSW [12ECF2-17]
- NHMRC [1037323]
- National Health and Medical Research Council of Australia [1074033] Funding Source: NHMRC
The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron-sulfur cluster (ISC) and heme synthesis. The inherited neuro-and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
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