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

Dioguardi, Carola Conca; Uslu, Bahar; Haynes, M. Page; Kuruş, Meltem; Gül, Mehmet; Miao, De Qiang; Santis, Lucia De; Ferrari, Maurizio; Bellone, Stefania; Santin, Alessandro D.; Giulivi, Cecilia R; Hoffman, Gloria E.; Usdin, Karen; Johnson, Joshua

doi:10.1093/molehr/gaw023

Cited by 56 publications

(45 citation statements)

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“…These results are consistent with findings showing that altered ratios of MDRS components lead to deficiencies in several Complexes including I and IV (OMIM 613076) (38). To explore whether the above deficits were ascribed to increases in mitochondrial mass, intrinsic 25,47). Altered mitochondrial network and dynamics have been noted in fibroblasts from carriers (20) and neurons from a knock-in (KI) mouse model of FMR1 premutation (23).…”

Section: Impaired Redox-regulated Mitochondrial Disulfide Relay Systesupporting

confidence: 84%

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Song¹,

Napoli²,

Wong³

et al. 2016

Mol Med

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A 55-200 expansion of the CGG nucleotide repeat in the 5′-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with age-and sex-matched controls (n = 25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTASaffected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome-and/or carrierspecific. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset. online address: http://www.molmed.org

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Section: Impaired Redox-regulated Mitochondrial Disulfide Relay Systesupporting

confidence: 84%

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Song¹,

Napoli²,

Wong³

et al. 2016

Mol Med

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“…Human data for FMR1 mRNA-associated toxicity in granulosa cells or oocytes is currently lacking. However, extrapolation of the findings of Conca Dioguardi et al [30] to the realm of human reproduction, specifically IVF, may possibly expound why poor oocyte and/or embryo quality is encountered in FMR1 pre-mutation carriers undergoing IVF [10][11][12] .…”

Section: Discussionmentioning

confidence: 95%

“…Despite the associations highlighted in the study, putative mechanisms of mRNA toxicity were not presented. In a mouse model of fragile X primary ovarian insufficiency, Conca Dioguardi et al [30] demonstrated that the deleterious effects of FMR1 mRNA are predominantly in the mitochondria of granulosa cells or oocytes. Specifically, the granulosa cells and oocytes in these mice had structurally aberrant mitochondria, lower mitochondrial content, and decreased expression of vital mitochondrial genes.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the granulosa cells and oocytes in these mice had structurally aberrant mitochondria, lower mitochondrial content, and decreased expression of vital mitochondrial genes. The developmental competence of these oocytes was impaired due to abnormal granulosaoocyte interactions [31] as well as intrinsic oocyte dysfunction, resulting in smaller litter sizes [30] . Human data for FMR1 mRNA-associated toxicity in granulosa cells or oocytes is currently lacking.…”

Section: Discussionmentioning

confidence: 99%

“…First, the study did not identify the mechanisms underlying the observed results. Although mechanisms arising from mouse models were appraised, we remain cautious about the existence of parallel mechanisms in humans [30] . Second, our findings do not delineate whether the impairment in blastocyst development begins with the oocyte and with post-fertilization events, or if it specifically occurs between days 3 and 5 of embryo development.…”

Section: Discussionmentioning

confidence: 99%

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Impact of <b><i>FMR1</i></b> Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis

Hutchinson

Pereira

Lilienthal

et al. 2017

Gynecol Obstet Invest

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Background/Aims: The study aimed to investigate the impact of fragile X mental retardation 1 (FMR1) pre-mutation status on blastocyst development in patients undergoing pre-implantation genetic diagnosis (PGD). Methods: Case-control study of patients <40 years undergoing PGD at blastocyst stage for FMR1 pre-mutation status. Age-matched patients undergoing PGD for other single gene disorders were considered controls. Blastocyst development, calculated per metaphase II (MII) oocyte retrieved and per 2 pronuclear (2PN) embryos, was compared between the 2 groups. Pregnancy outcomes after embryo transfer were also compared. Results: Eighty-one and 791 patients were included in the FMR1 and control groups, respectively. FMR1 pre-mutation carriers had lower indicators of ovarian reserve, required higher gonadotropin doses, and had fewer MII oocytes retrieved. Mean blastocyst development per MII oocyte (12.6 vs. 29.4%; p < 0.001) and per 2PN embryos (21.5 vs. 41.7%; p < 0.001) was lower in the FMR1 group. An inverse correlation between the number of FMR1 CGG repeats and blastocyst development per MII oocyte (ρ = -0.63; p < 0.001) was observed. There was no difference in the rates of clinical pregnancy, spontaneous abortion, or live birth among the groups. Conclusion: Our study suggests lower rates of blastocyst development in patients with FMR1 pre-mutation status and an inverse correlation between the number of FMR1 CGG repeats and blastocyst development.

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An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency

Rose

Brown

2020

J Assist Reprod Genet

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

Abstract: Studies were supported by 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.). No conflict(s) of interest or competing interest(s) are noted.

Cited by 56 publications

References 58 publications

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Impact of <b><i>FMR1</i></b> Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis

An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency

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