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Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

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.

SUBMITTER: Slone JD

PROVIDER: S-EPMC7272433 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

Slone Jesse D JD Yang Li L Peng Yanyan Y Queme Luis F LF Harris Belinda B Rizzo Stacey J Sukoff SJS Green Torrian T Ryan Jennifer L JL Jankowski Michael P MP Reinholdt Laura G LG Huang Taosheng T

Cell death & disease 20200604 6

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 ...[more]

PMID: 32499495

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Project description:BackgroundTo identify potential immune-related biomarkers, molecular mechanism, and therapeutic agents of intracranial aneurysms (IAs).MethodsWe identified the differentially expressed genes (DEGs) between IAs and control samples from GSE75436, GSE26969, GSE6551, and GSE13353 datasets. We used weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis to identify immune-related hub genes. We evaluated the expression of hub genes by using qRT-PCR analysis. Using miRNet, NetworkAnalyst, and DGIdb databases, we analyzed the regulatory networks and potential therapeutic agents targeting hub genes. Least absolute shrinkage and selection operator (LASSO) logistic regression was performed to identify optimal biomarkers among hub genes. The diagnostic value was validated by external GSE15629 dataset.ResultsWe identified 227 DEGs and 22 differentially infiltrating immune cells between IAs and control samples from GSE75436, GSE26969, GSE6551, and GSE13353 datasets. We further identified 41 differentially expressed immune-related genes (DEIRGs), which were primarily enriched in the chemokine-mediated signaling pathway, myeloid leukocyte migration, endocytic vesicle membrane, chemokine receptor binding, chemokine activity, and viral protein interactions with cytokines and their receptors. Among 41 DEIRGs, 10 hub genes including C3AR1, CD163, CCL4, CXCL8, CCL3, TLR2, TYROBP, C1QB, FCGR3A, and FCGR1A were identified with good diagnostic values (AUC >0.7). Hsa-mir-27a-3p and transcription factors, including YY1 and GATA2, were identified the primary regulators of hub genes. 92 potential therapeutic agents targeting hub genes were predicted. C3AR1 and CD163 were finally identified as the best diagnostic biomarkers using LASSO logistic regression (AUC = 0.994). The diagnostic value of C3AR1 and CD163 was validated by the external GSE15629 dataset (AUC = 0.914).ConclusionsThis study revealed the importance of C3AR1 and CD163 in immune infiltration in IAs pathogenesis. Our finding provided a valuable reference for subsequent research on the potential targets for molecular mechanisms and intervention of IAs.

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Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

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Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

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