Ferredoxin is a small, acidic, iron-sulfur protein that functions as an electron transport intermediate for mitochondrial
cytochromes P450 involved in steroid, vitamin D, and bile acid metabolism. Electrons are transferred from NADPH
through a flavin-containing protein (ferredoxin oxidoreductase) and ferredoxin to the terminal cytochrome P450 for
oxidation/reduction reactions. Mitochondrial P450s and their ferredoxin are found mainly in the steroidogenic tissues,
including adrenal, ovary and placenta.(Jefcoate et al., 1986).
NCBI Summary:
The product of this gene is a small iron-sulfur protein that transfers electrons from NADPH through ferredoxin reductase to a terminal cytochrome P450. This particular oxidation/reduction system is found in steroidogenic tissues, and is involved with the synthesis of bile acid and vitamin D. In addition to the expressed gene at this chromosomal locus (11q22), there are pseudogenes located on chromosomes 20 and 21. This gene product has been identified in a number of different tissues but all forms have been shown to be identical and are not tissue specific.
General function
Enzyme, Oxidoreductase
Comment
Cellular localization
Mitochondrial
Comment
Ovarian function
Steroid metabolism
Comment
Transcriptional regulation of human ferredoxin 1 in ovarian granulosa cells. Imamichi Y et al. Ferredoxin 1 (FDX1; adrenodoxin) is an iron-sulfur protein that is involved in various metabolic processes, including steroid hormone synthesis in mammalian tissues. We investigated the transcriptional regulation of FDX1 in ovarian granulosa cells. Previously, we reported that the NR5A family, including steroidogenic factor-1 (SF-1) and liver receptor homolog-1 could induce differentiation of human mesenchymal stem cells (hMSCs) into steroidogenic cells. A ChIP assay showed that SF-1 could bind to the FDX1 promoter in differentiated hMSCs. Luciferase reporter assays showed that transcription of FDX1 was synergistically activated by the NR5A family and 8Br-cAMP treatment through two SF-1 binding sites and a CRE-like sequence in a human ovarian granulosa cell line, KGN. Knockdown of FDX1 attenuated progesterone production in KGN cells. These results indicate transcription of FDX1 is regulated by the NR5A family and cAMP signaling, and participates in steroid hormone production in ovarian granulosa cells.
Funkenstein B, et al reported the induction of synthesis of cholesterol side chain cleavage cytochrome P-450 and
adrenodoxin by follicle-stimulating hormone, 8-bromo-cyclic AMP, and low
density lipoprotein in cultured bovine granulosa cells.
Expression regulated by
FSH, LH
Comment
Aflalo L et al reported the hormonal regulation of cholesterol side-chain cleavage
cytochrome P450, adrenodoxin, and their messenger ribonucleic
acid expression in bovine small-like and large-like luteal cells. The content of the side-chain
cleavage (SCC) enzymes cytochrome P450scc and adrenodoxin (ADX) and the
steady state availability of their mRNAs were determined and compared to P4
production in each of the luteal cell types. Small-like (SLC) and large-like (LLC)
luteal cells were obtained by incubating theca interna and granulosa cells with
forskolin and insulin. Upon luteinization, LLC expressed 2- to 3-fold higher
amounts of both SCC enzyme mRNAs than did SLC. Moreover, 8 days after
stimulant removal, LLC retained their P4 production capacity, expressed P450scc
and ADX mRNAs, and contained these proteins. In the SLC, P4 production, P450scc and ADX content, and their
mRNAs showed a much stronger dependence on chronic cAMP (and insulin)
stimulation.
McLean MP et al 1992 reported differential capacity for cholesterol transport and processing in
large and small rat luteal cells.
Large luteal cell
of the rat, in contrast to the small cell type, undergoes a dramatic increase in
protein content with luteal development, and that with this increase in cell size
there is a concomitant increase in the large cell capacity to produce steroids. This
occurs as a direct result of the enhanced expression of SCP2, P450scc,
adrenodoxin and adrenodoxin reductase, proteins specifically required to
transport and process cholesterol for steroid production in the large luteal cell.
Golos TG, et al reported that human chorionic gonadotropin and 8-bromo cyclic adenosine monophosphate
promote an acute increase in cytochrome P450scc and adrenodoxin messenger
RNAs in cultured human granulosa cells by a cycloheximide-insensitive
mechanism.
Ovarian localization
Cumulus, Granulosa, Theca, Luteal cells, Small luteal cells, Large luteal cells
Comment
Voutilainen R, et al studied hormonal and developmental regulation of adrenodoxin
messenger ribonucleic acid in steroidogenic tissues.
. Adrenodoxin mRNA was found in all
steroidogenic tissues examined. Unlike P450scc, however,
significant amounts of adrenodoxin mRNA were detected in human fetal ovaries,
with no discernible gestation-dependent change. The abundance of adrenodoxin
mRNA was increased in cultured human granulosa cells by treatment with hCG,
FSH, cAMP, and cholera toxin. In cultured fetal rhesus monkey ovarian cells, both hCG and
cAMP stimulated accumulation of adrenodoxin mRNA. In all of these systems, the
accumulation of adrenodoxin mRNA closely paralleled the response of P450scc.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.