Abstract
The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron–sulfur clusters and for steroidogenesis. Iron–sulfur (Fe–S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe–S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS). Inflammation and peripheral neuropathy are also hallmarks of this disease. In this paper, we demonstrate that FDXR mutation leads to significant optic transport defects that are likely to underlie optic atrophy, a major clinical presentation in FDXR patients, as well as a neurodegenerative loss of cells in the central nervous system (CNS). Molecular analysis indicates that FDXR mutation also leads to mitochondrial iron overload and an associated depolarization of the mitochondrial membrane, further supporting the hypothesis that FDXR mutations cause neurodegeneration by affecting FDXR’s critical role in iron homeostasis.
Highlights
Iron overload is a frequently observed occurrence in many mitochondrial diseases, as well as a common cause for neurological disorders
To better characterize the optic neuropathy associated with ferredoxin reductase (FDXR) mutation, we examined the retina of FdxrR389Q/R389Q mutant mice with an imaging technique, optical coherence tomography (OCT), that can acquire cross-sectional tomographic images of the retina in vivo[23,24]
Quantitative measurements indicated that the average thickness of the whole retina and ganglion cell complex (GCC)—which includes the nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)—were decreased in Fdxr−/− compared with Fdxr+/+ control mice at 10.5 months (Fig. 1b)
Summary
Iron overload is a frequently observed occurrence in many mitochondrial diseases, as well as a common cause for neurological disorders. There is an entire class of rare, inherited neurodegenerative diseases referred to as NBIA (neurodegeneration with brain iron accumulation), which are characterized by a progressive neurodegeneration phenotype linked with an abnormal and distinct accumulation of iron in the basal ganglia[9,10,11,12]. Together, all of these lines of evidence suggest that dysregulated iron metabolism may be a recurring theme in neurodegenerative disorders
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