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1.
BJOG ; 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39373298

RESUMEN

BACKGROUND: Endometriosis diagnosis reportedly faces delays of up to 10 years. Despite growing awareness and improved guidelines, information on the current status is limited. OBJECTIVES: To systematically assess the published evidence on the status of time to diagnosis in individuals with endometriosis, with respect to the definition of time to diagnosis, geographical location and patient characteristics. SEARCH STRATEGY: MEDLINE (via PubMed) and Embase were searched for publications reporting time to diagnosing endometriosis since 2018. No restrictions to population or comparators were applied. All publications were screened by two independent reviewers. SELECTION CRITERIA: Search results were limited to primary publications of randomised controlled trials, non-randomised trials and observational studies. Case reports, secondary publications and grey literature were excluded. No restrictions were made regarding language, provided that an English title and abstract were available. DATA COLLECTION AND ANALYSIS: Publications were assessed with respect to time to diagnosis, diagnostic methods, study type, study country and potential bias. MAIN RESULTS: The 17 publications eligible for inclusion in this literature review were all observational studies. The publications reported diagnosis times between 0.3 and 12 years, with variations depending on the definition of time to diagnosis (overall, primary, or clinical), geographical location and characteristics of the included study population. Evidence was of poor to good quality overall. CONCLUSIONS: Diagnostic delay is still present, primarily driven by physicians, and this review underscores the need for standardised definitions, increased awareness and targeted diagnostic interventions.

2.
Gynecol Endocrinol ; 39(1): 2166032, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36690019

RESUMEN

OBJECTIVE: To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40. METHODS: In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight. RESULTS: Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9-13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6-15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01-0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03-0.18). No differential effect on mood and weight was observed between cohorts. CONCLUSIONS: NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women.


Asunto(s)
Norpregnadienos , Tromboembolia Venosa , Embarazo , Femenino , Humanos , Anticonceptivos Orales Combinados/efectos adversos , Etinilestradiol , Estradiol , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/epidemiología , Megestrol
3.
Gynecol Endocrinol ; 39(1): 2162036, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36617423

RESUMEN

Objective: To investigate unintended pregnancy and changes in mood, acne, and weight in NOMAC-E2 vs levonorgestrel-containing COC (COCLNG) users under 25 years.Methods: In this large, observational study, new users (first-ever users of an eligible COC or restarting with the same or a new eligible COC after a break of at least 2 months) of NOMAC-E2 and COCLNG were recruited in 12 countries in Europe, Australia, and Latin America and followed up via questionnaires for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 women-years). Crude (HRcrude) and adjusted hazard ratios (HRadj) were calculated. Mood and acne changes were defined as change of score from baseline. Weight change was defined as percent change of body weight.Results: Overall, 12,829 NOMAC-E2 users and 17,095 COCLNG users under 25 were followed-up. The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort; confirmed events: 30 NOMAC-E2 (PI 0.24; 95% CI, 0.16-0.35) vs 94 COCLNG (PI 0.51; 95% CI, 0.41-0.62). The HRcrude for unintended pregnancy comparing NOMAC-E2 to COCLNG was 0.47 (95% CI, 0.31-0.71) and the HRadj was 0.52 (95% CI, 0.34-0.78). No differential effect on acne, mood, and weight was observed between cohorts.Conclusions: NOMAC-E2 shows a significantly better contraceptive effectiveness in young women and has no differential effect on acne, mood, and weight compared to COCLNG.


Asunto(s)
Acné Vulgar , Anticonceptivos Orales Combinados , Embarazo , Femenino , Humanos , Estradiol , Efectividad Anticonceptiva , Megestrol , Levonorgestrel , Acné Vulgar/tratamiento farmacológico
4.
Pharmacol Res ; 138: 43-56, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30219582

RESUMEN

Parkin, an E3 ubiquitin ligase and a Parkinson's disease (PD) related gene, translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy. Mitochondrial pro-fusion protein Mitofusins (Mfn1 and Mfn2) were found to be a target for Parkin mediated ubiquitination. Mfns are transmembrane GTPase embedded in the outer membrane of mitochondria, which are required on adjacent mitochondria to mediate fusion. In mammals, Mfn2 also forms complexes that are capable of tethering mitochondria to endoplasmic reticulum (ER), a structural feature essential for mitochondrial energy metabolism, calcium (Ca2+) transfer between the organelles and Ca2+ dependent cell death. Despite its fundamental physiological role, the molecular mechanisms that control ER-mitochondria cross talk are obscure. Ubiquitination has recently emerged as a powerful tool to modulate protein function, via regulation of protein subcellular localization and protein ability to interact with other proteins. Ubiquitination is also a reversible mechanism, which can be actively controlled by opposing ubiquitination-deubiquitination events. In this work we found that in Parkin deficient cells and parkin mutant human fibroblasts, the tether between ER and mitochondria is decreased. We identified the site of Parkin dependent ubiquitination and showed that the non-ubiquitinatable Mfn2 mutant fails to restore ER-mitochondria physical and functional interaction. Finally, we took advantage of an established in vivo model of PD to demonstrate that manipulation of ER-mitochondria tethering by expressing an ER-mitochondria synthetic linker is sufficient to rescue the locomotor deficit associated to an in vivo Drosophila model of PD.


Asunto(s)
Retículo Endoplásmico/fisiología , GTP Fosfohidrolasas/fisiología , Mitocondrias/fisiología , Proteínas Mitocondriales/fisiología , Enfermedad de Parkinson/fisiopatología , Ubiquitina-Proteína Ligasas/fisiología , Animales , Drosophila , Femenino , Fibroblastos/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Persona de Mediana Edad , Interferencia de ARN , ARN Interferente Pequeño/genética , Ubiquitinación
5.
J Biol Chem ; 290(8): 4537-4544, 2015 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-25550160

RESUMEN

Mitochondria of Drosophila melanogaster undergo Ca(2+)-induced Ca(2+) release through a putative channel (mCrC) that has several regulatory features of the permeability transition pore (PTP). The PTP is an inner membrane channel that forms from F-ATPase, possessing a conductance of 500 picosiemens (pS) in mammals and of 300 pS in yeast. In contrast to the PTP, the mCrC of Drosophila is not permeable to sucrose and appears to be selective for Ca(2+) and H(+). We show (i) that like the PTP, the mCrC is affected by the sense of rotation of F-ATPase, by Bz-423, and by Mg(2+)/ADP; (ii) that expression of human cyclophilin D in mitochondria of Drosophila S2R(+) cells sensitizes the mCrC to Ca(2+) but does not increase its apparent size; and (iii) that purified dimers of D. melanogaster F-ATPase reconstituted into lipid bilayers form 53-pS channels activated by Ca(2+) and thiol oxidants and inhibited by Mg(2+)/γ-imino ATP. These findings indicate that the mCrC is the PTP of D. melanogaster and that the signature conductance of F-ATPase channels depends on unique structural features that may underscore specific roles in different species.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Adenosina Trifosfatasas/genética , Animales , Canales de Calcio/genética , Línea Celular , Proteínas de Drosophila/genética , Drosophila melanogaster , Humanos , Proteínas de Transporte de Membrana Mitocondrial/genética , Poro de Transición de la Permeabilidad Mitocondrial
6.
Neurobiol Dis ; 90: 58-67, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26550693

RESUMEN

Mitochondria are double membrane-bounded organelles residing in the cytoplasm of almost all eukaryotic cells, which convert energy from the disposal of organic substrates into an electrochemical gradient that is in turn converted into ATP. However, the ion gradient that is generated through the oxidation of nutrients, may lead to the production of reactive oxygen species (ROS), which can generate free radicals, damaging cells and contributing to disease. Originally described as static structures, to date they are considered extremely plastic and dynamic organelles. In this respect, mitochondrial dynamics is crucial to prevent potential damage that is generated by ROS. For instance, mitochondria elongate to dilute oxidized proteins into the mitochondrial network, and they fragment to allow selective elimination of dysfunctional mitochondria via mitophagy. Accordingly, mitochondrial dynamics perturbation may compromise the selective elimination of damaged proteins and dysfunctional organelles and lead to the development of different diseases including neurodegenerative diseases. In recent years the fruit fly Drosophila melanogaster has proved to be a valuable model system to evaluate the consequences of mitochondria quality control dysfunction in vivo, particularly with respect to PINK1/Parkin dependent dysregulation of mitophagy in the onset of Parkinson's Disease (PD). The current challenge is to be able to use fly based genetic strategies to gain further insights into molecular mechanisms underlying disease in order to develop new therapeutic strategies. This article is part of a Special Issue entitled: Role of mitochondria in physiological and pathophysiological functions in the central nervous system.


Asunto(s)
Dinámicas Mitocondriales/fisiología , Mitofagia/fisiología , Trastornos Parkinsonianos/metabolismo , Animales , Drosophila melanogaster , Humanos , Dinámicas Mitocondriales/efectos de los fármacos , Mitofagia/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico
7.
Proc Natl Acad Sci U S A ; 110(15): 5887-92, 2013 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-23530243

RESUMEN

Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalk of the FOF1 ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca(2+) like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca(2+). Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca(2+), addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg(2+)/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.


Asunto(s)
Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Animales , Apoptosis , Calcio/metabolismo , Bovinos , Línea Celular Tumoral , Dimerización , Humanos , Hidrólisis , Potenciales de la Membrana , Ratones , Mitocondrias Hepáticas/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , ARN Interferente Pequeño/metabolismo , Transfección
8.
J Biol Chem ; 289(42): 29235-46, 2014 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-25164807

RESUMEN

Leigh Syndrome (LS) is the most common early-onset, progressive mitochondrial encephalopathy usually leading to early death. The single most prevalent cause of LS is occurrence of mutations in the SURF1 gene, and LS(Surf1) patients show a ubiquitous and specific decrease in the activity of mitochondrial respiratory chain complex IV (cytochrome c oxidase, COX). SURF1 encodes an inner membrane mitochondrial protein involved in COX assembly. We established a Drosophila melanogaster model of LS based on the post-transcriptional silencing of CG9943, the Drosophila homolog of SURF1. Knockdown of Surf1 was induced ubiquitously in larvae and adults, which led to lethality; in the mesodermal derivatives, which led to pupal lethality; or in the central nervous system, which allowed survival. A biochemical characterization was carried out in knockdown individuals, which revealed that larvae unexpectedly displayed defects in all complexes of the mitochondrial respiratory chain and in the F-ATP synthase, while adults had a COX-selective impairment. Silencing of Surf1 expression in Drosophila S2R(+) cells led to selective loss of COX activity associated with decreased oxygen consumption and respiratory reserve. We conclude that Surf1 is essential for COX activity and mitochondrial function in D. melanogaster, thus providing a new tool that may help clarify the pathogenic mechanisms of LS.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Enfermedad de Leigh/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Complejos de ATP Sintetasa/metabolismo , Animales , Línea Celular , Proteínas de Drosophila/fisiología , Transporte de Electrón , Complejo IV de Transporte de Electrones/metabolismo , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Potencial de la Membrana Mitocondrial , Proteínas de la Membrana/fisiología , Mifepristona/química , Mitocondrias/enzimología , Proteínas Mitocondriales/fisiología , Mutación , Oxígeno/metabolismo , Interferencia de ARN , Procesamiento Postranscripcional del ARN , ARN Bicatenario/química , Transcripción Genética
9.
Obstet Gynecol ; 143(3): 431-434, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38227942

RESUMEN

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.


Asunto(s)
Anticonceptivos Orales Combinados , Estradiol/análogos & derivados , Nandrolona/análogos & derivados , Tromboembolia Venosa , Femenino , Humanos , Anticonceptivos Orales Combinados/efectos adversos , Levonorgestrel , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/epidemiología , Estudios Prospectivos , Etinilestradiol/efectos adversos , Estradiol/efectos adversos , Valeratos , Combinación de Medicamentos
10.
Artículo en Inglés | MEDLINE | ID: mdl-39461741

RESUMEN

BACKGROUND: The etonogestrel (ENG) subdermal implant is considered a well-tolerated and effective contraception option to avoid unintended pregnancies. However, it is unclear whether being affected by overweight or obesity diminishes the effectiveness of the implant. OBJECTIVES: To systematically assess the published evidence on implant contraceptive effectiveness in women with overweight or obesity, and in women who underwent bariatric surgery. SEARCH STRATEGY: A systematic search of MEDLINE and Embase for publications reporting implant effectiveness since 2011. SELECTION CRITERIA: Primary publications of randomised and non-randomised trials, observational studies and case reports were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers identified the Pearl Index, qualitative descriptions of contraceptive failure, implant exposure and potential bias, and assessed overall quality of evidence. MAIN RESULTS: We found 12 publications meeting our criteria, consisting of nine observational studies and three case reports. Excluding case reports, the publications reported Pearl Indices from 0.0/100 women-years (WY) to 0.23/100WY for women with overweight and obesity, respectively. No studies met the eligibility criteria for the post-bariatric surgery population. CONCLUSIONS: Observed implant effectiveness in women with overweight and obesity falls within the range of published data across all weight groups (0.0-1.4/100 WY) and does not suggest a reduced effectiveness associated with higher body mass index. Large, well-controlled studies designed to specifically assess the effectiveness of the ENG implant with respect to user weight, particularly in women following bariatric surgery, are warranted.

11.
Cell Death Differ ; 31(2): 217-238, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38238520

RESUMEN

Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.


Asunto(s)
Calcineurina , Proteínas de Drosophila , Animales , Calcineurina/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Mitofagia/genética , Mitocondrias/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Drosophila/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
12.
J Biol Chem ; 286(48): 41163-41170, 2011 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-21984833

RESUMEN

We have studied the pathways for Ca(2+) transport in mitochondria of the fruit fly Drosophila melanogaster. We demonstrate the presence of ruthenium red (RR)-sensitive Ca(2+) uptake, of RR-insensitive Ca(2+) release, and of Na(+)-stimulated Ca(2+) release in energized mitochondria, which match well characterized Ca(2+) transport pathways of mammalian mitochondria. Following larger matrix Ca(2+) loading Drosophila mitochondria underwent spontaneous RR-insensitive Ca(2+) release, an event that in mammals is due to opening of the permeability transition pore (PTP). Like the PTP of mammals, Drosophila Ca(2+)-induced Ca(2+) release could be triggered by uncoupler, diamide, and N-ethylmaleimide, indicating the existence of regulatory voltage- and redox-sensitive sites and was inhibited by tetracaine. Unlike PTP-mediated Ca(2+) release in mammals, however, it was (i) insensitive to cyclosporin A, ubiquinone 0, and ADP; (ii) inhibited by P(i), as is the PTP of yeast mitochondria; and (iii) not accompanied by matrix swelling and cytochrome c release even in KCl-based medium. We conclude that Drosophila mitochondria possess a selective Ca(2+) release channel with features intermediate between the PTP of yeast and mammals.


Asunto(s)
Calcio/metabolismo , Proteínas de Drosophila/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Difosfato/farmacología , Animales , Antifúngicos/farmacología , Benzoquinonas/farmacología , Ciclosporina/farmacología , Drosophila melanogaster , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/fisiología , Indicadores y Reactivos/farmacología , Transporte Iónico/efectos de los fármacos , Transporte Iónico/fisiología , Mamíferos/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Rojo de Rutenio/farmacología , Especificidad de la Especie , Levaduras/metabolismo
13.
AJOG Glob Rep ; 2(1): 100041, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36274960

RESUMEN

BACKGROUND: Norethisterone (acetate) and levonorgestrel are marketed globally as components of combined oral contraceptives. Although guidelines recommend both as first-line combined oral contraceptives, no direct, comparative safety studies are available. OBJECTIVE: We directly compared the thromboembolic event risk associated with the use of norethisterone acetate-containing and levonorgestrel-containing combined oral contraceptives. STUDY DESIGN: Data regarding the cohorts of interest, norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg) and levonorgestrel (ethinylestradiol ≤30 µg), were retrieved from a pooled dataset comprising 4 prospective, noninterventional, active-surveillance cohort studies in 14 European countries, the United States, and Canada, with similar study design but differing medication cohorts. Baseline characteristics and parameters of reproductive, contraceptive, and medical history were summarized using descriptive statistics. Propensity score subclassification was applied to balance baseline parameters between cohorts. Time-to-event analysis of venous thromboembolic events was performed on the basis of the extended Cox model to calculate crude and adjusted hazard ratios, including 95% confidence intervals. The time of venous thromboembolic events was censored at the end of the observation period for women who did not have an event. Women who dropped out or were lost to follow-up without reported venous thromboembolic events were censored at the time they last confirmed that they did not have an event. RESULTS: The pooled dataset included 235,437 combined oral contraceptive users who were followed up for a total of 571,163 women years. Among these, 40,142 women were users of norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg), and 39,098 women were users of levonorgestrel (ethinylestradiol ≤30 µg), contributing 61,976 and 84,816 women years of observation, respectively. The observed prevalence of prognostic factors at baseline showed typical features of US and European combined oral contraceptive users. Both cohorts showed a similar, low rate of thromboembolic events, and we could exclude a 1.5-fold increased venous thromboembolism risk for norethisterone/norethisterone acetate relative to levonorgestrel (adjusted hazard ratio, 0.73; 95% confidence interval, 0.48-1.11). CONCLUSION: These data confirm the similar risk profiles of norethisterone/norethisterone acetate and levonorgestrel regarding thromboembolic events in routine combined oral contraceptive use of around 80,000 women from Europe and the United States/Canada. The analysis provides reassurance for both combined oral contraceptive users and clinicians regarding the safety of oral contraceptives and potentially opens discussion on norethisterone acetate as a potential gold standard therapy in clinical and postmarket research alongside levonorgestrel-combined oral contraceptives.

14.
Aging Cell ; 20(6): e13379, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34061429

RESUMEN

Increased levels of dysfunctional mitochondria within skeletal muscle are correlated with numerous age-related physiopathological conditions. Improving our understanding of the links between mitochondrial function and muscle proteostasis, and the role played by individual genes and regulatory networks, is essential to develop treatments for these conditions. One potential player is the mitochondrial outer membrane protein Fis1, a crucial fission factor heavily involved in mitochondrial dynamics in yeast but with an unknown role in higher-order organisms. By using Drosophila melanogaster as a model, we explored the effect of Fis1 mutations generated by transposon Minos-mediated integration. Mutants exhibited a higher ratio of damaged mitochondria with age as well as elevated reactive oxygen species levels compared with controls. This caused an increase in oxidative stress, resulting in large accumulations of ubiquitinated proteins, accelerated muscle function decline, and mitochondrial myopathies in young mutant flies. Ectopic expression of Fis1 isoforms was sufficient to suppress this phenotype. Loss of Fis1 led to unbalanced mitochondrial proteostasis within fly muscle, decreasing both flight capabilities and lifespan. Fis1 thus clearly plays a role in fly mitochondrial dynamics. Further investigations into the detailed function of Fis1 are necessary for exploring how mitochondrial function correlates with muscle health during aging.


Asunto(s)
Drosophila melanogaster/genética , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Proteostasis/genética , Envejecimiento , Animales
15.
Eur J Obstet Gynecol Reprod Biol ; 251: 212-217, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32559605

RESUMEN

OBJECTIVE: Dienogest (DNG) 2 mg (Visanne) was launched for endometriosis treatment in Europe in 2010. The Visanne Post-approval Observational Study (VIPOS) was designed to assess the safety of DNG 2 mg/day compared to other hormonal endometriosis treatments, focusing especially on clinically relevant depression and anemia. STUDY DESIGN: Large, prospective, non-interventional, active surveillance study in six European countries. Participants were recruited via gynecologists or specialized centers routinely prescribing endometriosis medication. Self-administered questionnaires during study entry and follow-up collected information on baseline characteristics, health status and endometriosis treatment. Patient-reported anemia and depression cases were validated by health care professionals. Inferential statistics were based on Cox proportional hazards models and crude and adjusted hazard ratios (HR) between cohorts were calculated (including 95% confidence intervals [CI]). Adjustment for potential confounding was performed by including predefined prognostic factors as covariates in the Cox models. RESULTS: Out of 26,430 participants, 11.4% used DNG, 12.8% used other approved endometriosis medications (OAED) and 75.7% used hormonal treatments not approved but frequently used for endometriosis treatment (NAED). At baseline, DNG users more frequently reported a surgically confirmed endometriosis diagnosis, severe endometriosis-associated pain and a history of depression, compared to the other cohorts. Baseline characteristics showed large inter-country variability. Overall, the number of confirmed anemia and depression events were substantially lower than expected. The adjusted HRs for anemia were 1.1 (95% CI, 0.4-2.6) for DNG vs OAED and 1.3 (95% CI, 0.7-2.4) for DNG vs NAED. The adjusted HRs for new or worsening depression were 1.8 (95% CI, 0.3-9.4) for DNG vs OAED and 1.5 (95% CI, 0.8-2.8) for DNG vs NAED. CONCLUSION: The main limitations encountered (low number of confirmed events and considerable inter-country variability) made a robust statistical analysis and a solid interpretation of the results challenging. However, no safety signal regarding anemia for DNG users could be detected, whereas a slight increase in depression risk cannot be excluded but might be explained by baseline severity of endometriosis or unknown country-specific confounding variables. VIPOS reflected routine use of hormonal endometriosis medications and provided real-world insights into endometriosis management in Europe.


Asunto(s)
Anemia , Endometriosis , Nandrolona , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Anemia/epidemiología , Depresión/tratamiento farmacológico , Depresión/epidemiología , Endometriosis/complicaciones , Endometriosis/tratamiento farmacológico , Endometriosis/epidemiología , Europa (Continente) , Femenino , Humanos , Estudios Prospectivos
16.
Redox Biol ; 37: 101676, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32956978

RESUMEN

UCH-L1 is a deubiquitinating enzyme (DUB), highly abundant in neurons, with a sub-cellular localization dependent on its farnesylation state. Despite UCH-L1's association with familial Parkinson's Disease (PD), the effects on mitochondrial bioenergetics and quality control remain unexplored. Here we investigated the role of UCHL-1 in mitochondrial dynamics and bioenergetics. We demonstrate that knock-down (KD) of UCH-L1 in different cell lines reduces the levels of the mitochondrial fusion protein Mitofusin-2, but not Mitofusin-1, resulting in mitochondrial enlargement and disruption of the tubular network. This was associated with lower tethering between mitochondria and the endoplasmic reticulum, consequently altering mitochondrial calcium uptake. Respiratory function was also altered, as UCH-L1 KD cells displayed higher proton leak and maximum respiratory capacity. Conversely, overexpression of UCH-L1 increased Mfn2 levels, an effect dramatically enhanced by the mutation of the farnesylation site (C220S), which drives UCH-L1 binding to membranes. These data indicate that the soluble cytosolic form of UCH-L1 regulates Mitofusin-2 levels and mitochondrial function. These effects are biologically conserved, since knock-down of the corresponding UCH-L1 ortholog in D. melanogaster reduces levels of the mitofusin ortholog Marf and also increases mitochondrial respiratory capacity. We thus show that Mfn-2 levels are directly affected by UCH-L1, demonstrating that the mitochondrial roles of DUBs go beyond controlling mitophagy rates.


Asunto(s)
Calcio , Drosophila melanogaster , Mitocondrias , Ubiquitina Tiolesterasa , Animales , Transporte Biológico , Calcio/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Retículo Endoplásmico/metabolismo , GTP Fosfohidrolasas , Mitocondrias/genética , Mitocondrias/metabolismo , Ubiquitina Tiolesterasa/metabolismo
17.
Methods Mol Biol ; 1925: 233-243, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30674031

RESUMEN

In the presence of Ca2+, F-ATP synthase preparations eluted from Blue Native gels generate electrophysiological currents that are typical of an inner mitochondrial membrane mega-channel, the permeability transition pore. Here we describe an experimental protocol for purification of F-ATP synthase that allows to maintain the enzyme assembly and activity that are essential for catalysis and channel formation.


Asunto(s)
Mitocondrias/enzimología , ATPasas de Translocación de Protón Mitocondriales/aislamiento & purificación , Electroforesis en Gel de Poliacrilamida Nativa/métodos , Animales , Western Blotting/métodos , Drosophila , Electroforesis en Gel de Poliacrilamida/métodos , Células HeLa , Humanos , Ratones , ATPasas de Translocación de Protón Mitocondriales/química , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Multimerización de Proteína , Colorantes de Rosanilina/química , Coloración y Etiquetado/métodos
18.
Cell Rep ; 27(5): 1541-1550.e5, 2019 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-31042479

RESUMEN

Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Mutación , Animales , Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Transporte de Catión/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Fenotipo
19.
Life Sci Alliance ; 2(2)2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30988163

RESUMEN

Aberrant mitochondrial dynamics disrupts mitochondrial function and contributes to disease conditions. A targeted RNA interference screen for deubiquitinating enzymes (DUBs) affecting protein levels of multifunctional mitochondrial fusion protein Mitofusin (MFN) identified USP8 prominently influencing MFN levels. Genetic and pharmacological inhibition of USP8 normalized the elevated MFN protein levels observed in PINK1 and Parkin-deficient models. This correlated with improved mitochondrial function, locomotor performance and life span, and prevented dopaminergic neurons loss in Drosophila PINK1 KO flies. We identified a novel target antagonizing pathologically elevated MFN levels, mitochondrial dysfunction, and dopaminergic neuron loss of a Drosophila model of mitochondrial dysfunction.


Asunto(s)
Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimología , Proteínas de la Membrana/metabolismo , Mitocondrias/enzimología , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Proteasas Ubiquitina-Específicas/antagonistas & inhibidores , Proteasas Ubiquitina-Específicas/metabolismo , Animales , Línea Celular , Dimetilsulfóxido/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Regulación hacia Abajo/genética , Drosophila , Drosophila melanogaster/embriología , Silenciador del Gen , Longevidad , Masculino , Mitocondrias/patología , Enfermedad de Parkinson/metabolismo , Fenotipo , Transducción de Señal/efectos de los fármacos , Transfección , Proteasas Ubiquitina-Específicas/genética
20.
EMBO Mol Med ; 10(11)2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30249595

RESUMEN

Mitochondrial autophagy or mitophagy is a key process that allows selective sequestration and degradation of dysfunctional mitochondria to prevent excessive reactive oxygen species, and activation of cell death. Recent studies revealed that ubiquitin-proteasome complex activity and mitochondrial membrane rupture are key steps preceding mitophagy, in combination with the ubiquitination of specific outer mitochondrial membrane (OMM) proteins. The deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy. Here, we report that genetic and pharmacological inhibition of USP14 promotes mitophagy, which occurs in the absence of the well-characterised mediators of mitophagy, PINK1 and Parkin. Critical to USP14-induced mitophagy is the exposure of the LC3 receptor Prohibitin 2 by mitochondrial fragmentation and mitochondrial membrane rupture. Genetic or pharmacological inhibition of USP14 in vivo corrected mitochondrial dysfunction and locomotion behaviour of PINK1/Parkin mutant Drosophila model of Parkinson's disease, an age-related progressive neurodegenerative disorder that is correlated with diminished mitochondrial quality control. Our study identifies a novel therapeutic target that ameliorates mitochondrial dysfunction and in vivo PD-related symptoms.


Asunto(s)
Proteínas de Drosophila/metabolismo , Mitofagia , Modelos Biológicos , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismo , Animales , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Línea Celular Tumoral , Respiración de la Célula , Drosophila , Técnicas de Silenciamiento del Gen , Humanos , Lisosomas/metabolismo , Lisosomas/ultraestructura , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Actividad Motora
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