RESUMO
Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.
Assuntos
Autofagia , Mitofagia , Animais , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , Lipídeos , Mamíferos/metabolismoRESUMO
Male germline development involves choreographed changes to mitochondrial number, morphology and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
Assuntos
Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , Proteínas Mitocondriais/metabolismo , Mitofagia/genética , Espermátides/metabolismo , Espermatogênese/genética , Animais , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genéticaRESUMO
Nearly forty years have passed since the Chornobyl Nuclear Power Plant accident, which resulted in childhood and adolescent thyroid cancers increasing due to internal exposure to iodine-131. Therefore, the Fukushima Daiichi Nuclear Power Station accident, in 2011, raised serious anxiety about potential risks of thyroid cancers. Considering the causal relationship between thyroid cancer and the Chornobyl accident, radiation dose to the thyroid due to this accident should be considered carefully. In addition, a thorough investigation of any influence of ultrasound screening of the thyroid on the detection of thyroid diseases was still missing. Consequently, from 2019 to 2021, the frequency of abnormal thyroid findings from screening of residents in Zhytomyr, Ukraine, which was heavily contaminated by the accident, was evaluated in this study. For this, the same diagnostic classification of any thyroid ultrasound findings as those of the Fukushima Health Management Survey were used. This classification used the categories "A1" (no findings), "A2" (thyroid cysts less than 20 mm and/or thyroid nodules less than 5 mm), and "B" (thyroid cysts more than 20 mm and/or thyroid nodules more than 5 mm). 2,978 participants were analyzed. It was found that the frequency of "B" findings increased with age. This may be due to the observed increased incidence of not only malignant but also benign thyroid nodules. It may well be that such an increase will also be observed in Fukushima in the future. It is concluded that future thyroid examiners in Fukushima should be aware of findings specific to adults, such as chronic thyroiditis. For comparison, it will be necessary to perform longitudinal studies in the Japanese population not exposed to radiation from the Fukushima accident.
Assuntos
Acidente Nuclear de Chernobyl , Glândula Tireoide , Ultrassonografia , Humanos , Adulto , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/efeitos da radiação , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Ucrânia/epidemiologia , Adolescente , Centrais Nucleares , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Acidente Nuclear de FukushimaRESUMO
AIMS/HYPOTHESIS: Mitophagy, the selective autophagy of mitochondria, is essential for maintenance of mitochondrial function. Recent studies suggested that defective mitophagy in beta cells caused diabetes. However, because of technical difficulties, the development of a convenient and reliable method to evaluate mitophagy in beta cells in vivo is needed. The aim of this study was to establish beta cell-specific mitophagy reporter mice and elucidate the role of mitophagy in beta cell function under metabolically stressed conditions induced by a high-fat diet (HFD). METHODS: Mitophagy was assessed using newly generated conditional mitochondrial matrix targeting mitophagy reporter (CMMR) mice, in which mitophagy can be visualised specifically in beta cells in vivo using a fluorescent probe sensitive to lysosomal pH and degradation. Metabolic stress was induced in mice by exposure to the HFD for 20 weeks. The accumulation of dysfunctional mitochondria was examined by staining for functional/total mitochondria and reactive oxygen species (ROS) using specific fluorescent dyes and antibodies. To investigate the molecular mechanism underlying mitophagy in beta cells, overexpression and knockdown experiments were performed. HFD-fed mice were examined to determine whether chronic insulin treatment for 6 weeks could ameliorate mitophagy, mitochondrial function and impaired insulin secretion. RESULTS: Exposure to the HFD increased the number of enlarged (HFD-G) islets with markedly elevated mitophagy. Mechanistically, HFD feeding induced severe hypoxia in HFD-G islets, which upregulated mitophagy through the hypoxia-inducible factor 1-É (Hif-1É)/BCL2 interacting protein 3 (BNIP3) axis in beta cells. However, HFD-G islets unexpectedly showed the accumulation of dysfunctional mitochondria due to excessive ROS production, suggesting an insufficient capacity of mitophagy for the degradation of dysfunctional mitochondria. Chronic administration of insulin ameliorated hypoxia and reduced ROS production and dysfunctional mitochondria, leading to decreased mitophagy and restored insulin secretion. CONCLUSIONS/INTERPRETATION: We demonstrated that CMMR mice enabled the evaluation of mitophagy in beta cells. Our results suggested that metabolic stress induced by the HFD caused the aberrant accumulation of dysfunctional mitochondria, which overwhelmed the mitophagic capacity and was associated with defective maintenance of mitochondrial function and impaired insulin secretion.
Assuntos
Mitocôndrias , Estresse Fisiológico , Camundongos , Animais , Insulina , HipóxiaRESUMO
Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin-mediated cell death through the FKBP38-dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin-induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.
Assuntos
Mitofagia , Ubiquitina-Proteína Ligases , Sobrevivência Celular , Células HeLa , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Muscle disuse induces atrophy through increased reactive oxygen species (ROS) released from damaged mitochondria. Mitophagy, the autophagic degradation of mitochondria, is associated with increased ROS production. However, the mitophagy activity status during disuse-induced muscle atrophy has been a subject of debate. Here, we developed a new mitophagy reporter mouse line to examine how disuse affected mitophagy activity in skeletal muscles. Mice expressing tandem mCherry-EGFP proteins on mitochondria were then used to monitor the dynamics of mitophagy activity. The reporter mice demonstrated enhanced mitophagy activity and increased ROS production in atrophic soleus muscles following a 14-day hindlimb immobilization. Results also showed an increased expression of multiple mitophagy genes, including Bnip3, Bnip3l, and Park2. Our findings thus conclude that disuse enhances mitophagy activity and ROS production in atrophic skeletal muscles and suggests that mitophagy is a potential therapeutic target for disuse-induced muscle atrophy.
Assuntos
Mitocôndrias Musculares/metabolismo , Mitofagia , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Elevação dos Membros Posteriores , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Inanição , Fatores de Tempo , Proteína Vermelha FluorescenteRESUMO
Mitochondrial quality control maintains mitochondrial function by regulating mitochondrial dynamics and mitophagy. Despite the identification of mitochondrial quality control factors, little is known about the crucial regulators coordinating both mitochondrial fission and mitophagy. Through a cell-based functional screening assay, FK506 binding protein 8 (FKBP8) was identified to target microtubule-associated protein 1 light chain 3 (LC3) to the mitochondria and to change mitochondrial morphology. Microscopy analysis revealed that the formation of tubular and enlarged mitochondria was observed in FKBP8 knockdown HeLa cells and the cortex of Fkbp8 heterozygote-knockout mouse embryos. Under iron depletion-induced stress, FKBP8 was recruited to the site of mitochondrial division through budding and colocalized with LC3. FKBP8 was also found to be required for mitochondrial fragmentation and mitophagy under hypoxic stress. Conversely, FKBP8 overexpression induced mitochondrial fragmentation in HeLa cells, human fibroblasts and mouse embryo fibroblasts (MEFs), and this fragmentation occurred in Drp1 knockout MEF cells, FIP200 knockout HeLa cells and BNIP3/NIX double knockout HeLa cells, but not in Opa1 knockout MEFs. Interestingly, we found an LIR motif-like sequence (LIRL), as well as an LIR motif, at the N-terminus of FKBP8 and LIRL was essential for both inducing mitochondrial fragmentation and binding of FKBP8 to OPA1. Together, we suggest that FKBP8 plays an essential role in mitochondrial fragmentation through LIRL during mitophagy and this activity of FKBP8 together with LIR is required for mitophagy under stress conditions.
Assuntos
Fibroblastos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Estresse Fisiológico , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/genética , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).
Assuntos
Adipócitos/patologia , Adipogenia , Antirretrovirais/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Diferenciação Celular , Estresse do Retículo Endoplasmático , Lipodistrofia/induzido quimicamente , Células-Tronco/patologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/patologia , Terapia Antirretroviral de Alta Atividade , Apoptose/efeitos dos fármacos , Sulfato de Atazanavir/farmacologia , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dano ao DNA , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fator de Transcrição CHOP/metabolismoRESUMO
The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10-20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 "internal radiation therapy" of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3-5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.
Assuntos
Hipotireoidismo , Neoplasias da Glândula Tireoide , Adulto , Relação Dose-Resposta à Radiação , Humanos , Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologia , Radioisótopos do IodoRESUMO
BACKGROUND: After the Fukushima Daiichi Nuclear Power Plant accident, a preliminary ultrasound-based screening for thyroid cancer was conducted to establish a baseline for subsequent evaluations. In this survey, we assessed the relationship between the proportion of non-examinees and characteristics of the target populations. METHODS: After summarizing a regional difference of non-examinees among the population of 359,200 (primary evaluation) and 2,246 (confirmatory testing) individuals who were living in Fukushima Prefecture on March 11, 2011, we estimated odds ratios (ORs) for each characteristic, including age, sex, area of residence, and moving after the accident, based on the proportion of non-examinees for the primary examination and the confirmatory testing, using a multivariate logistic regression model. RESULTS: The dataset included 64,117 non-examinees (primary evaluation) and 194 (confirmatory testing). The logistic regression result indicated that girls were not likely to be non-examinees compared to boys, with adjusted OR of 0.80 (95% confidence interval [CI], 0.78-0.81) for the primary evaluation. Odds were lowest for children 6-10 years old (OR 0.26; 95% CI, 0.25-0.27), and higher for those 11-15 years old (OR 1.28; 95% CI, 1.25-1.32) and over 16 years old (OR 5.30; 95% CI, 5.16-5.43) when compared to children 0-5 years old. Individuals residing in the western part of the prefecture showed higher ORs. There was a higher proportion of non-examinees among those who moved after the accident compared to those who did not in the primary evaluation (OR 1.72; 95% CI, 1.64-1.79). CONCLUSIONS: In addition to demographic characteristics, a change of residence could be a potential factor that influenced the proportion of non-examinees. Our results will help proper interpretation of reports and prospective management of the survey.
Assuntos
Acidente Nuclear de Fukushima , Programas de Rastreamento/estatística & dados numéricos , Neoplasias da Glândula Tireoide/diagnóstico , Ultrassonografia/métodos , Criança , Pré-Escolar , Feminino , Inquéritos Epidemiológicos , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Estudos Prospectivos , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
AIM: After the Great East Japan Earthquake, over 160,000 residents in Fukushima Prefecture were forced to evacuate the area around the Fukushima Daiichi power plant following nuclear accident there. Health problems in these evacuees have since become a major issue. We have examined the association between evacuation and incidence of hyperuricemia among residents in Fukushima. METHODS: We conducted a cohort study of residents aged 40-90 years without hyperuricemia at the time of the Fukushima disaster. Among 8173 residents who met the inclusion criteria before the disaster, 4789 residents (men: 1971, women: 2818; follow-up duration: 1.38 years; and follow-up rate: 58.6%) remained available for follow-up examinations at the end of March 2013. The main endpoint was incidence of hyperuricemia, defined by the Japanese committee guidelines, using local health data from before and after the disaster. We divided participants by evacuation status and compared outcomes between groups. Using a logistic regression model, we estimated the odds ratio for incidence of hyperuricemia, adjusting for potential confounders, age, gender, waist circumference, physical activity, and alcohol consumption. RESULTS: Incidence of hyperuricemia was higher in evacuees (men 10.1%; women 1.1%) than in non-evacuees (men 7.4%, women 1.0%). Evacuees had higher body mass index, waist circumference, triglycerides, LDL-cholesterol, fasting plasma glucose, HbA1c, and lower HDL-cholesterol after the disaster than non-evacuees. We found that evacuation was associated with incidence of hyperuricemia (adjusted odds ratio: 1.38; 95% confidence interval: 1.03-1.86). CONCLUSION: This is the first study to demonstrate an association between evacuation after a disaster and increased incidence of hyperuricemia.
Assuntos
Vítimas de Desastres/estatística & dados numéricos , Acidente Nuclear de Fukushima , Hiperuricemia/epidemiologia , Ácido Úrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Inquéritos Epidemiológicos , Humanos , Hiperuricemia/sangue , Incidência , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Trabalho de Resgate , Fatores Sexuais , Triglicerídeos/sangue , Circunferência da CinturaRESUMO
Thyroid ultrasound screening of young residents in Fukushima Prefecture, Japan, showed a high detection rate of papillary thyroid carcinoma (PTC). Detailed morphological analysis of these tumors was not presented to date. This study sets out to evaluate changes in histopathological and invasive characteristics of Fukushima PTC with time after the nuclear accident of March 2011 in all available cases and in different age subgroups. Histological specimens of 115 PTCs from patients aged 18 years or younger at the time of the Fukushima Dai-ichi Nuclear Power Plant accident, who underwent surgical resection at Fukushima Medical University during 2012-2016, were reviewed. Patients were divided into those treated during the first 4 years after the accident (n = 78, shorter-onset) or later (n = 37, longer-onset). The whole group and 3 age subgroups: children (aged less than 15 years), adolescents (aged from 15 to less than 19 years), and young adults (aged from 19 years) at surgery were analyzed. No statistically significant time-related changes in tumor structure or invasiveness were found in the whole group or in age-matched subgroups. Statistically significant age-related downtrend was observed for intrathyroid spread in the whole group of patients. The absence of temporal changes in tumor morphological characteristics and tumor invasiveness strongly suggests common etiology of the shorter- and longer-onset Fukushima PTCs, which are unlikely related to the effect of exposure to very low doses of radiation.
Assuntos
Carcinoma/patologia , Neoplasias Induzidas por Radiação/patologia , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Feminino , Acidente Nuclear de Fukushima , Humanos , Japão , Masculino , Programas de Rastreamento/métodos , Neoplasias Induzidas por Radiação/diagnóstico , Doses de Radiação , Ultrassonografia/métodos , Adulto JovemRESUMO
Genetic mutations play important roles in not only development of papillary thyroid carcinoma (PTC) but also determination of its properties. The radioactive iodine refractory (RAIR) state is a harbinger of poor outcomes for PTC. We used various statistical models to investigate the significance of TERT promoter, BRAF, and RAS mutations in distinguishing the RAIR state and their associations with 131 I uptake. Mutations were examined in primary lesions of 33 RAIR cases and 34 age- and sex-matched 131 I-treated cases with disease-free status. Thyrotropin-stimulated thyroglobulin (sTg) change, 131 I uptake ability, and RAIR categories were evaluated in the RAIR cases. The prevalence of TERT mutation in the RAIR group was 24.24% (8/33), which was significantly higher than that in the disease-free group (0/34). BRAF mutation showed a similar high prevalence in both the RAIR group (69.70%) and disease-free group (64.71%). Among the eight TERT mutation-positive cases, six carried both TERT and BRAF mutations. RAS mutation was detected in only one disease-free case and in two RAIR cases. Despite a significantly higher prevalence of TERT mutations in the RAIR group, only tumor size and N1b lymph node involvement were independently associated with RAIR status. In the RAIR group, all patients carrying a TERT mutation showed maximum or increased sTg. Multivariate analyses demonstrated that the TERT mutation was associated with decreased 131 I uptake and the RAIR categories of absent or weaker 131 I uptake. TERT mutation constitutes a novel genetic biomarker indicating absent or weaker 131 I-avid lesions in RAIR PTC patients. It is worth evaluating the TERT status in all DTC patients undergoing 131 I therapy. © 2019 IUBMB Life, 2019.
Assuntos
Marcadores Genéticos , Radioisótopos do Iodo/metabolismo , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/radioterapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
BACKGROUND: The 2011 Great East Japan Earthquake led to a nuclear accident at Fukushima Daiichi Nuclear Power Plant. This study examines the associations of radiation dose and lifestyle factors with incidence of thyroid cancer in Fukushima. METHODS: We designed a prospective study with 300,473 participants aged 18 years or younger, who underwent thyroid examinations from October 2011. Follow-up surveys were conducted through June 2017, and 245,530 participants (123,480 men and 122,050 women, 82% follow-up) received follow-up examinations. Fukushima Prefecture was divided into five areas based on individual external radiation dose. We calculated relative risks and 95% confidence intervals (CIs) for thyroid cancer in each area, with area of lowest dose as reference, using age-adjusted Poisson regression models. We also calculated risks associated with overweight and obesity. RESULTS: The incidence per 100,000 for Groups A (highest dose), B, C, D, and E (lowest dose) were 13.5, 19.2, 17.3, 9.0, and 8.3, respectively. Compared with Group E, the age-adjusted risks (95% CIs) were 1.62 (0.59, 4.47) for group A, 2.32 (0.86, 6.24) for group B, 2.21 (0.82, 5.94) for group C, and 1.02 (0.36, 2.86) for group D. Obesity was positively associated with thyroid cancer incidence; the multivariable-adjusted risk of thyroid cancer was 2.23 (1.01, 4.90) for obese individuals compared with nonobese individuals. CONCLUSION: Regional differences in radiation dose were not associated with increased risk of thyroid cancer among children in Fukushima within 4 to 6 years after the nuclear power plant accident. Obesity may be an important factor for further follow-up in Fukushima.
Assuntos
Carcinoma/epidemiologia , Acidente Nuclear de Fukushima , Obesidade/epidemiologia , Doses de Radiação , Neoplasias da Glândula Tireoide/epidemiologia , Adolescente , Carcinoma/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Análise Multivariada , Neoplasias da Glândula Tireoide/diagnóstico por imagem , UltrassonografiaRESUMO
A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to pave the way for a new solution to the regenerative approaches. Limitations in the reconstructive surgeries in restoring tissue loss and deficiency have paved the way for new regenerative approaches. Among them, adipose-derived stem/progenitor cells (ADSCs)-based therapy could be the most promising clue, since ADSCs have pluripotent differentiation capabilities not only in adipocytes but also in a variety of cell types. Accumulating evidences have indicated that the unfavorable development of adipose-tissue damage, namely, lipodystrophy, is a systemic complication, which is closely related to metabolic abnormality. Considering ADSC-based regenerative medicine should be applied for the treatment of lipodystrophy, it is inevitable to ascertain whether the ADSCs obtained from the patients with lipodystrophy are capable of being used. It will be very promising and realistic if this concept is applied to lipoatrophy; one form of lipodystrophies that deteriorates the patients' quality of life because of excessive loss of soft tissue in the exposed areas such as face and extremities. Since lipodystrophy is frequently observed in the human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART), the present study aims to examine the biological potentials of ADSCs isolated from the HIV-infected patients with lipodystrophy associated with the HAART treatment. Growth properties, adipogenic differentiation, and mitochondrial reactive oxygen species (ROS) production were examined in ADSCs from HIV-infected and HIV-uninfected patients. Our results clearly demonstrated that ADSCs from both patients showed indistinguishable growth properties and potentials for adipocyte differentiation in vitro. Thus, although the number of cases were limited, ADSCs isolated from the patients with lipodystrophy retain sufficient physiological and biological activity for the reconstitution of adipose-tissue, suggesting that ADSCs from the patients with lipodystrophy could be used for autologous ADSC-based regenerative therapy.
Assuntos
Adipogenia , Tecido Adiposo/citologia , Lipodistrofia/terapia , Células-Tronco/citologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Células Cultivadas , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Lipodistrofia/induzido quimicamente , Masculino , Transplante de Células-Tronco , Cicatrização , Adulto JovemRESUMO
Nucleotide excision repair (NER) is the most versatile DNA repair system that deals with the major UV photoproducts in DNA, as well as many other DNA adducts. The early steps of NER are well understood, whereas the later steps of repair synthesis and ligation are not. In particular, which polymerases are definitely involved in repair synthesis and how they are recruited to the damaged sites has not yet been established. We report that, in human fibroblasts, approximately half of the repair synthesis requires both pol kappa and pol delta, and both polymerases can be recovered in the same repair complexes. Pol kappa is recruited to repair sites by ubiquitinated PCNA and XRCC1 and pol delta by the classical replication factor complex RFC1-RFC, together with a polymerase accessory factor, p66, and unmodified PCNA. The remaining repair synthesis is dependent on pol epsilon, recruitment of which is dependent on the alternative clamp loader CTF18-RFC.
Assuntos
Dano ao DNA , Reparo do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Fibroblastos/enzimologia , ATPases Associadas a Diversas Atividades Celulares , Proteínas de Transporte/metabolismo , Linhagem Celular , Senescência Celular , DNA Polimerase II/metabolismo , DNA Polimerase III/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , Fibroblastos/efeitos da radiação , Humanos , Proteínas Nucleares/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , Antígeno Nuclear de Célula em Proliferação/metabolismo , Processamento de Proteína Pós-Traducional , Transporte Proteico , Interferência de RNA , Proteínas Recombinantes de Fusão/metabolismo , Proteína de Replicação C/metabolismo , Fatores de Tempo , Transfecção , Ubiquitina-Proteína Ligases , Ubiquitinação , Raios Ultravioleta , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
Phosphatase and tensin homolog-induced putative kinase 1 (PINK1), a Ser/Thr kinase, and PARKIN, a ubiquitin ligase, are causal genes for autosomal recessive early-onset parkinsonism. Multiple lines of evidence indicate that PINK1 and PARKIN cooperatively control the quality of the mitochondrial population via selective degradation of damaged mitochondria by autophagy. Here, we report that PINK1 and PARKIN induce cell death with a 12-h delay after mitochondrial depolarization, which differs from the time profile of selective autophagy of mitochondria. This type of cell death exhibited definite morphologic features such as plasma membrane rupture, was insensitive to a pan-caspase inhibitor, and did not involve mitochondrial permeability transition. Expression of a constitutively active form of PINK1 caused cell death in the presence of a pan-caspase inhibitor, irrespective of the mitochondrial membrane potential. PINK1-mediated cell death depended on the activities of PARKIN and proteasomes, but it was not affected by disruption of the genes required for autophagy. Furthermore, fluorescence and electron microscopic analyses revealed that mitochondria were still retained in the dead cells, indicating that PINK1-mediated cell death is not caused by mitochondrial loss. Our findings suggest that PINK1 and PARKIN play critical roles in selective cell death in which damaged mitochondria are retained, independent of mitochondrial autophagy.
Assuntos
Mitocôndrias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases/metabolismo , Morte Celular , Células HEK293 , Células HeLa , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Peroxisome number and quality are maintained by its biogenesis and turnover and are important for the homeostasis of peroxisomes. Peroxisomes are increased in number by division with dynamic morphological changes including elongation, constriction, and fission. In the course of peroxisomal division, peroxisomal morphogenesis is orchestrated by Pex11ß, dynamin-like protein 1 (DLP1), and mitochondrial fission factor (Mff). Conversely, peroxisome number is reduced by its degradation. Peroxisomes are mainly degraded by pexophagy, a type of autophagy specific for peroxisomes. Upon pexophagy, an adaptor protein translocates on peroxisomal membrane and connects peroxisomes to autophagic machineries. Molecular mechanisms of pexophagy are well studied in yeast systems where several specific adaptor proteins are identified. Pexophagy in mammals also proceeds in a manner dependent on adaptor proteins. In this review, we address the recent progress in studies on peroxisome morphogenesis and pexophagy.
Assuntos
Retículo Endoplasmático/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Peroxissomos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitina/metabolismo , Animais , Dinaminas , Retículo Endoplasmático/química , Células Eucarióticas/química , Células Eucarióticas/metabolismo , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/genética , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Peroxinas , Peroxissomos/química , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Proteólise , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Especificidade da Espécie , Ubiquitina/genética , Leveduras/química , Leveduras/metabolismoRESUMO
BACKGROUND: The Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident caused residents to switch from their normal lives to lives focused on evacuation. We evaluated liver function before and after this disaster to elucidate the effects of evacuation on liver function. METHODS: This study was a longitudinal survey of 26,006 Japanese men and women living near the Fukushima Daiichi Nuclear Power Plant. This study was undertaken using data from annual health checkups conducted for persons aged 40-90 years between 2008 and 2010. Follow-up examinations were conducted from June 2011 to the end of March 2013, with a mean follow up of 1.6 years. Changes in liver function before and after the disaster were compared among evacuees and non-evacuees. We also assessed groups according to alcohol drinking status. RESULTS: The prevalence of liver dysfunction significantly increased in all participants from 16.4% before to 19.2% after the disaster. The incidence of liver dysfunction was significantly higher in evacuees than in non-evacuees. Multivariate logistic regression analysis showed that evacuation was significantly associated with liver dysfunction among residents. CONCLUSIONS: This is the first study to show that evacuation due to the Fukushima Daiichi nuclear power plant disaster was associated with an increase in liver dysfunction.