Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency

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dc.authoridGiulivi, Cecilia/0000-0003-1033-7435
dc.authoridGül, Mehmet/0000-0002-1374-0783
dc.authoridGiulivi, Cecilia/0000-0003-1033-7435
dc.authoridFerrari, Maurizio/0000-0002-1721-801X
dc.authoridBellone, Stefania/0000-0001-5909-5292
dc.authoridJohnson, Joshua/0000-0002-6016-8089
dc.authoridConca Dioguardi, Carola/0000-0001-5335-031X
dc.authorwosidDe Santis, Lucia/ABI-2166-2020
dc.authorwosidGiulivi, Cecilia/AAV-6774-2021
dc.authorwosidUslu, Bahar/H-4903-2016
dc.authorwosidJohnson, Johnson/HDL-9124-2022
dc.authorwosidGül, Mehmet/ABI-6336-2020
dc.authorwosidGiulivi, Cecilia/ABB-7809-2020
dc.authorwosidHoffman, Gloria E/AAU-3760-2021
dc.contributor.authorDioguardi, Carola Conca
dc.contributor.authorUslu, Bahar
dc.contributor.authorHaynes, Monique
dc.contributor.authorKurus, Meltem
dc.contributor.authorGul, Mehmet
dc.contributor.authorMiao, De-Qiang
dc.contributor.authorDe Santis, Lucia
dc.date.accessioned2024-08-04T20:41:50Z
dc.date.available2024-08-04T20:41:50Z
dc.date.issued2016
dc.departmentİnönü Üniversitesien_US
dc.description.abstractSTUDY HYPOTHESIS: We hypothesized that the mitochondria of granulosa cells (GC) and/or oocytes might be abnormal in a mouse model of fragile X premutation (FXPM). STUDY FINDING: Mice heterozygous and homozygous for the FXPM have increased death (atresia) of large ovarian follicles, fewer corpora lutea with a gene dosage effect manifesting in decreased litter size(s). Furthermore, granulosa cells (GC) and oocytes of FXPM mice have decreased mitochondrial content, structurally abnormal mitochondria, and reduced expression of critical mitochondrial genes. Because this mouse allele produces the mutant Fragile X mental retardation 1 (Fmr1) transcript and reduced levels of wild-type (WT) Fmr1 protein (FMRP), but does not produce a Repeat Associated Non-ATG Translation (RAN)-translation product, our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. WHAT IS KNOWN ALREADY: Mitochondrial dysfunction has been detected in somatic cells of human and mouse FXPM carriers and mitochondria are essential for oogenesis and ovarian follicle development, FX-associated primary ovarian insufficiency (FXPOI) is seen in women with FXPM alleles. These alleles have 55-200 CGG repeats in the 5' UTR of an X-linked gene known as FMR1. The molecular basis of the pathology seen in this disorder is unclear but is thought to involve either some deleterious consequence of overexpression of RNA with long CGG-repeat tracts or of the generation of a repeat-associated non-AUG translation (RAN translation) product that is toxic. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Analysis of ovarian function in a knock-in FXPM mouse model carrying 130 CGG repeats was performed as follows on WT, PM/+, and PM/PM genotypes. Histomorphometric assessment of follicle and corpora lutea numbers in ovaries from 8-month-old mice was executed, along with litter size analysis. Mitochondrial DNA copy number was quantified in oocytes and GC using quantitative PCR, and cumulus granulosa mitochondrial content was measured by flow cytometric analysis after staining of cells with Mitotracker dye. Transmission electron micrographs were prepared of GC within small growing follicles and mitochondrial architecture was compared. Quantitative RT-PCR analysis of key genes involved in mitochondrial structure and recycling was performed. MAIN RESULTS AND THE ROLE OF CHANCE: A defect was found in follicle survival at the large antral stage in PM/+ and PM/PM mice. Litter size was significantly decreased in PM/PM mice, and corpora lutea were significantly reduced in mice of both mutant genotypes. Mitochondrial DNA copy number was significantly decreased in GC and metaphase II eggs in mutants. Flow cytometric analysis revealed that PM/+ and PM/PM animals lack the cumulus GC that harbor the greatest mitochondrial content as found in wild-type animals. Electron microscopic evaluation of GC of small growing follicles revealed mitochondrial structural abnormalities, including disorganized and vacuolar cristae. Finally, aberrant mitochondrial gene expression was detected. Mitofusin 2 (Mfn2) and Optic atrophy 1 (Opa1), genes involved in mitochondrial fusion and structure, respectively, were significantly decreased in whole ovaries of both mutant genotypes. Mitochondrial fission factor 1 (Mff1) was significantly decreased in PM/+ and PM/PM GC and eggs compared with wild-type controls. LIMITATIONS, REASONS FOR CAUTION: Data from the mouse model used for these studies should be viewed with some caution when considering parallels to the human FXPOI condition. WIDER IMPLICATIONS OF THE FINDINGS: Our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. FXPM disease states, including FXPOI, may share mitochondrial dysfunction as a common underlying mechanism. LARGE SCALE DATA: Not applicable.en_US
dc.description.sponsorshipNational Institutes of Health (NIH) [R21 071873]; Albert McKern Fund for Perinatal Research; NIH; TUBITAKen_US
dc.description.sponsorshipThese studies were supported by National Institutes of Health (NIH) R21 071873 (J.J., G.H.), The Albert McKern Fund for Perinatal Research (J.J.), NIH Intramural Funds (K.U.), and a TUBITAK Research Fellowship Award (B.U.).en_US
dc.identifier.doi10.1093/molehr/gaw023
dc.identifier.endpage396en_US
dc.identifier.issn1360-9947
dc.identifier.issn1460-2407
dc.identifier.issue6en_US
dc.identifier.pmid26965313en_US
dc.identifier.scopus2-s2.0-84975127273en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage384en_US
dc.identifier.urihttps://doi.org/10.1093/molehr/gaw023
dc.identifier.urihttps://hdl.handle.net/11616/97379
dc.identifier.volume22en_US
dc.identifier.wosWOS:000381205600002en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.relation.ispartofMolecular Human Reproductionen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectfragile X primary ovarian insufficiencyen_US
dc.subjectfragile X premutationen_US
dc.subjectovaryen_US
dc.subjectoocyteen_US
dc.subjectfollicleen_US
dc.subjectfertilityen_US
dc.subjectatresiaen_US
dc.subjectmitochondriaen_US
dc.titleGranulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiencyen_US
dc.typeArticleen_US

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