Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with dysfunction in Fe-S cluster biogenesis. The mitochondrial membrane-associated flavoprotein ferredoxin reductase (FDXR) provides electrons from NADPH for formation of the transient iron- sulfur cluster and carries out electron transport from NADPH to cytochrome P450 via ferrodoxin-1 or -2 (FDX1 or FDX2) in steroid hormone synthesis. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified a large number of individuals from the unrelated families with recessive FDXR mutations. In vitro enzymatic assays indicated FDXR mutations cause deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex II/III activities, and ATP production. More importantly, overexpression wild- type of FDXR can rescue the biochemical defects. Consistently, biochemical abnormalities and recapitulation of the clinical phenotype was observed in homozygous mutant Fxdr mice. This is the first report to associate FDXR mutations with human disease. FDXR as a critical early component of Fe-S cluster biogenesis and steroid hormone biosynthesis thus loss function could affect many downstream pathways and cause multiple organ dysfunctions. Here we propose: 1). To study biochemical mechanisms by which FDXR mutations cause mitochondrial dysfunction and abnormal Fe-S cluster synthesis. We will recruit additional families and to examine the genotype-phenotype correlation. We will test the ferredoxin NADP reduction activity and mitochondrial function in patient cells. The pathogenesis of mutant FDXR will also be tested in vitro by measuring the redox state and biogenesis of ferredoxin clusters, using site-specific mutagenesis and overexpressed mutant FDXR protein corresponding to the mutations identified in our patients. 2). To characterize an FDXR mouse model to study the molecular mechanisms of pathogenesis by evaluate optic atrophy and peripheral neuropathies via behavioral, histological and electrophysiological analysis (e.g. visual evoked potentials and electromyography) in currently available and CRISPR knock-in mouse model that precisely matches the common human mutation. 3). To assess the effect of FDXR mutations on steroid metabolism by examining steroid hormonal levels and cholesterol metabolite profiles in patient blood and in mouse models. In the future, these mouse models will be used to test therapeutic agents for treating this disease by supplementing the deficient products.

Public Health Relevance

With new genomic approach--whole exome sequencing approaches, we have identified the mutations in the FDXR gene associated with mitochondrial function. Here we propose to create a mouse model to study pathogenesis of FDXR mutations and elucidate the molecular mechanisms. The study will facilitate our understanding mechanism of FDXR mutations and develop a potential treatment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Liberman, Ellen S
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Cincinnati Children's Hospital Medical Center
United States
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