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1.
Cell ; 183(5): 1162-1184, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33242416

RESUMEN

Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.


Asunto(s)
Medio Ambiente Extraterrestre , Vuelo Espacial , Astronautas , Salud , Humanos , Microbiota , Factores de Riesgo
2.
Cell ; 183(5): 1185-1201.e20, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33242417

RESUMEN

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.


Asunto(s)
Genómica , Mitocondrias/patología , Vuelo Espacial , Estrés Fisiológico , Animales , Ritmo Circadiano , Matriz Extracelular/metabolismo , Humanos , Inmunidad Innata , Metabolismo de los Lípidos , Análisis de Flujos Metabólicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Músculos/inmunología , Especificidad de Órganos , Olfato/fisiología
4.
Cell ; 163(1): 33-8, 2015 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-26406369

RESUMEN

Environmental adaptation, predisposition to common diseases, and, potentially, speciation may all be linked through the adaptive potential of mitochondrial DNA (mtDNA) alterations of bioenergetics. This Perspective synthesizes evidence that human mtDNA variants may be adaptive or deleterious depending on environmental context and proposes that the accrual of mtDNA variation could contribute to animal speciation via adaptation to marginal environments.


Asunto(s)
ADN Mitocondrial/genética , Enfermedad/genética , Especiación Genética , Migración Humana , Animales , Femenino , Variación Genética , Genética Médica , Humanos , Fosforilación Oxidativa
5.
Cell ; 151(2): 333-343, 2012 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-23063123

RESUMEN

Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.


Asunto(s)
ADN Mitocondrial/genética , Ratones/genética , Animales , Conducta Animal , Cognición , Femenino , Patrón de Herencia , Masculino , Ratones/fisiología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Especificidad de la Especie
6.
Proc Natl Acad Sci U S A ; 121(30): e2321972121, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39008677

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.


Asunto(s)
Antioxidantes , COVID-19 , Ratones Transgénicos , Mitocondrias , Fosforilación Oxidativa , SARS-CoV-2 , Animales , Ratones , COVID-19/virología , COVID-19/metabolismo , COVID-19/inmunología , COVID-19/patología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Pulmón/virología , Pulmón/patología , Pulmón/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Catalasa/metabolismo , Catalasa/genética , Tratamiento Farmacológico de COVID-19 , Modelos Animales de Enfermedad , Inmunidad Innata
7.
Nature ; 571(7766): 515-520, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31341297

RESUMEN

The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.


Asunto(s)
Mitocondrias/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Protones , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Coenzimas/metabolismo , Ácidos Grasos/metabolismo , Transporte Iónico , Masculino , Ratones , Consumo de Oxígeno
8.
Nature ; 575(7782): 375-379, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31618756

RESUMEN

Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy1. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM232. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.


Asunto(s)
Mitofagia , Animales , Línea Celular , Ratones , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Nucleótidos/metabolismo , Unión Proteica , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo
9.
Proc Natl Acad Sci U S A ; 119(18): e2200549119, 2022 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-35482926

RESUMEN

Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.


Asunto(s)
Enfermedades Mitocondriales , Condicionamiento Físico Animal , Animales , Humanos , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mutación , Condicionamiento Físico Animal/fisiología , Resistencia Física/genética
10.
Proc Natl Acad Sci U S A ; 119(45): e2212417119, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36322731

RESUMEN

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.


Asunto(s)
ADN Mitocondrial , Histamina , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Haplotipos , Histamina/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Tejido Conectivo/metabolismo
11.
Glob Chang Biol ; 30(3): e17228, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38483025

RESUMEN

The mitigation of climate change and pollution-related hypoxia and anoxia is a growing challenge for coastal communities. Known ocean conservation measures do not show the desired fast results counteracting deoxygenation. The new infrastructure related to the coastal production of renewable energies linked to the production of green hydrogen can provide new possibilities of artificial ocean reoxygenation to mitigate coastal hypoxia, but has to be treated urgently and seriously from different scientific, engineering and socio-economic angles.


Asunto(s)
Cambio Climático , Ecosistema , Humanos , Contaminación Ambiental , Hipoxia
12.
Pharmacol Res ; 204: 107170, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38614374

RESUMEN

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.


Asunto(s)
COVID-19 , Mitocondrias , Fosforilación Oxidativa , SARS-CoV-2 , Humanos , COVID-19/metabolismo , COVID-19/genética , COVID-19/virología , Mitocondrias/metabolismo , Mitocondrias/genética , Especies Reactivas de Oxígeno/metabolismo , Epigénesis Genética , Metabolismo Energético , Epigenómica , Animales
13.
Proc Natl Acad Sci U S A ; 118(18)2021 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-33903227

RESUMEN

Nitrification is a central process of the aquatic nitrogen cycle that controls the supply of nitrate used in other key processes, such as phytoplankton growth and denitrification. Through time series observation and modeling of a seasonally stratified, eutrophic coastal basin, we demonstrate that physical dilution of nitrifying microorganisms by water column mixing can delay and decouple nitrification. The findings are based on a 4-y, weekly time series in the subsurface water of Bedford Basin, Nova Scotia, Canada, that included measurement of functional (amoA) and phylogenetic (16S rRNA) marker genes. In years with colder winters, more intense winter mixing resulted in strong dilution of resident nitrifiers in subsurface water, delaying nitrification for weeks to months despite availability of ammonium and oxygen. Delayed regrowth of nitrifiers also led to transient accumulation of nitrite (3 to 8 µmol · kgsw-1) due to decoupling of ammonia and nitrite oxidation. Nitrite accumulation was enhanced by ammonia-oxidizing bacteria (Nitrosomonadaceae) with fast enzyme kinetics, which temporarily outcompeted the ammonia-oxidizing archaea (Nitrosopumilus) that dominated under more stable conditions. The study reveals how physical mixing can drive seasonal and interannual variations in nitrification through control of microbial biomass and diversity. Variable, mixing-induced effects on functionally specialized microbial communities are likely relevant to biogeochemical transformation rates in other seasonally stratified water columns. The detailed study reveals a complex mechanism through which weather and climate variability impacts nitrogen speciation, with implications for coastal ecosystem productivity. It also emphasizes the value of high-frequency, multiparameter time series for identifying complex controls of biogeochemical processes in aquatic systems.


Asunto(s)
Nitrificación/genética , Ciclo del Nitrógeno/genética , Nitrosomonadaceae/genética , Agua/metabolismo , Amoníaco/metabolismo , Compuestos de Amonio/metabolismo , Archaea/genética , Archaea/metabolismo , Biomasa , Canadá , Desnitrificación/genética , Ecosistema , Humanos , Cinética , Nitratos , Nitritos/metabolismo , Nitrógeno/metabolismo , Nitrosomonadaceae/patogenicidad , Oxidación-Reducción , Filogenia , Fitoplancton/genética , Fitoplancton/metabolismo , ARN Ribosómico 16S/genética , Estaciones del Año
14.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33536343

RESUMEN

Autism spectrum disorders (ASDs) are characterized by a deficit in social communication, pathologic repetitive behaviors, restricted interests, and electroencephalogram (EEG) aberrations. While exhaustive analysis of nuclear DNA (nDNA) variation has revealed hundreds of copy number variants (CNVs) and loss-of-function (LOF) mutations, no unifying hypothesis as to the pathophysiology of ASD has yet emerged. Based on biochemical and physiological analyses, it has been hypothesized that ASD may be the result of a systemic mitochondrial deficiency with brain-specific manifestations. This proposal has been supported by recent mitochondrial DNA (mtDNA) analyses identifying both germline and somatic mtDNA variants in ASD. If mitochondrial defects do predispose to ASD, then mice with certain mtDNA mutations should present with autism endophenotypes. To test this prediction, we examined a mouse strain harboring an mtDNA ND6 gene missense mutation (P25L). This mouse manifests impaired social interactions, increased repetitive behaviors and anxiety, EEG alterations, and a decreased seizure threshold, in the absence of reduced hippocampal interneuron numbers. EEG aberrations were most pronounced in the cortex followed by the hippocampus. Aberrations in mitochondrial respiratory function and reactive oxygen species (ROS) levels were also most pronounced in the cortex followed by the hippocampus, but absent in the olfactory bulb. These data demonstrate that mild systemic mitochondrial defects can result in ASD without apparent neuroanatomical defects and that systemic mitochondrial mutations can cause tissue-specific brain defects accompanied by regional neurophysiological alterations.


Asunto(s)
Trastorno Autístico/genética , Encéfalo/metabolismo , ADN Mitocondrial/genética , Mitocondrias/genética , Animales , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Variaciones en el Número de Copia de ADN/genética , Modelos Animales de Enfermedad , Electroencefalografía , Endofenotipos , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Mitocondrias/patología , Mutación/genética , Especies Reactivas de Oxígeno/metabolismo
15.
J Sleep Res ; 32(6): e13847, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36872072

RESUMEN

Comorbid insomnia and sleep apnoea (COMISA) is a highly prevalent and debilitating sleep disorder. Cognitive behavioural therapy for insomnia (CBTi) may be an appropriate treatment for COMISA; however, no previous study has systematically reviewed and meta-analysed literature reporting on the effect of CBTi in people with COMISA. A systematic literature search was conducted across PsychINFO and PubMed (n = 295). In all, 27 full-text records were independently reviewed by at least two authors. Forward- and backward-chain referencing, and hand-searches were used to identify additional studies. Authors of potentially eligible studies were contacted to provide COMISA subgroup data. In total, 21 studies, including 14 independent samples of 1040 participants with COMISA were included. Downs and Black quality assessments were performed. A meta-analysis including nine primary studies measuring the Insomnia Severity Index indicated that CBTi is associated with a large improvement in insomnia severity (Hedges' g = -0.89, 95% confidence interval [CI] -1.35, -0.43). Subgroup meta-analyses indicated that CBTi is effective in samples with untreated obstructive sleep apnoea (OSA) (five studies, Hedges' g = -1.19, 95% CI -1.77, -0.61) and treated OSA (four studies, Hedges' g = -0.55, 95% CI -0.75, -0.35). Publication bias was evaluated by examining the Funnel plot (Egger's regression p = 0.78). Implementation programmes are required to embed COMISA management pathways in sleep clinics worldwide that currently specialise in the management of OSA alone. Future research should investigate and refine CBTi interventions in people with COMISA, including identifying the most effective CBTi components, adaptations, and developing personalised management approaches for this highly prevalent and debilitating condition.


Asunto(s)
Terapia Cognitivo-Conductual , Apnea Obstructiva del Sueño , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Sueño , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/terapia , Comorbilidad
16.
Curr Opin Pulm Med ; 29(6): 567-573, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37642477

RESUMEN

PURPOSE OF REVIEW: Insomnia and obstructive sleep apnea have previously been viewed as completely independent conditions. However, there is now increasing recognition that insomnia and sleep apnea frequently co-occur. Co-morbid insomnia and sleep apnea (COMISA) is a highly prevalent condition that is associated with impairment of sleep, daytime function, mental health and physical health outcomes, and mortality risk. This review aims to provide an update on COMISA prevalence, consequences, treatment approaches, and future research directions. RECENT FINDINGS: People with COMISA experience worse sleep, mental health, physical health, quality of life and longevity compared to people with neither condition, and often compared to those with insomnia alone and sleep apnea alone. Emerging evidence suggests that cognitive behavioral therapy for insomnia is an effective treatment in the presence of treated and untreated sleep apnea, that may also improve manifestations and subsequent management of sleep apnea. Future research is required to understand the etiology of COMISA, and to develop and implement tailored treatment approaches. SUMMARY: It is important for sleep and respiratory technicians, researchers and clinicians to be aware of the high co-morbidity rates, consequences, and treatment requirements of patients with co-morbid insomnia and sleep apnea.


Asunto(s)
Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Calidad de Vida , Síndromes de la Apnea del Sueño/epidemiología , Síndromes de la Apnea del Sueño/terapia , Comorbilidad , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/terapia
17.
Exp Brain Res ; 241(2): 427-440, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36574036

RESUMEN

Deep space flight missions will expose astronauts to multiple stressors, including sleep fragmentation and space radiation. There is debate over whether sleep disruptions are an issue in deep space. While these stressors independently impair sensorimotor function, the combined effects on performance are currently unknown. String-pulling behavior involves highly organized bimanual reach-to-grasp and withdraw movements. This behavior was examined under rested wakeful conditions and immediately following one session of sleep fragmentation in Sham and irradiated rats 3 months after exposure (10 cGy 4Helium or 5-ion simulated Galactic Cosmic Radiation). Sleep fragmentation disrupted several aspects of string-pulling behavior, such that rats' ability to grasp the string was reduced, reach endpoint concentration was more variable, and distance traveled by the nose increased in the Y-range compared to rested wakeful performance. Overall, irradiated rats missed the string more than Sham rats 3 months post-exposure. Irradiated rats also exhibited differential impairments at 3 months, with additional deficits unveiled after sleep fragmentation. 4Helium-exposed rats took longer to approach the string after sleep fragmentation. Further, rats exposed to 4Helium traveled shorter withdraw distances 3 months after irradiation, while this only emerged in the other irradiated group after sleep fragmentation. These findings identify sleep fragmentation as a risk for fine motor dysfunction in Sham and irradiated conditions, in addition to radiation exposure. There may be complex temporal alterations in performance that are stressor- and ion-dependent. Thus, it is critical to implement appropriate models of multi-flight stressors and performance assessments in preparation for future deep space flight missions.


Asunto(s)
Privación de Sueño , Vuelo Espacial , Ratas , Animales , Humanos , Privación de Sueño/complicaciones , Helio , Movimiento , Astronautas
18.
Proc Natl Acad Sci U S A ; 117(50): 32056-32065, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33257573

RESUMEN

MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function that directly activates cytochrome c oxidase in the mitochondria and functions in the nucleus as a transcriptional activator for hundreds of genes. Since MNRR1 depletion contains features of a mitochondrial disease phenotype, we evaluated the effects of forced expression of MNRR1 on the mitochondrial disease MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. MELAS is a multisystem encephalomyopathy disorder that can result from a heteroplasmic mutation in the mitochondrial DNA (mtDNA; m.3243A > G) at heteroplasmy levels of ∼50 to 90%. Since cybrid cell lines with 73% m.3243A > G heteroplasmy (DW7) display a significant reduction in MNRR1 levels compared to the wild type (0% heteroplasmy) (CL9), we evaluated the effects of MNRR1 levels on mitochondrial functioning. Overexpression of MNRR1 in DW7 cells induces the mitochondrial unfolded protein response (UPRmt), autophagy, and mitochondrial biogenesis, thereby rescuing the mitochondrial phenotype. It does so primarily as a transcription activator, revealing this function to be a potential therapeutic target. The role of MNRR1 in stimulating UPRmt, which is blunted in MELAS cells, was surprising and further investigation uncovered that under conditions of stress the import of MNRR1 into the mitochondria was blocked, allowing the protein to accumulate in the nucleus to enhance its transcription function. In the mammalian system, ATF5, has been identified as a mediator of UPRmt MNRR1 knockout cells display an ∼40% reduction in the protein levels of ATF5, suggesting that MNRR1 plays an important role upstream of this known mediator of UPRmt.


Asunto(s)
Núcleo Celular/metabolismo , ADN Mitocondrial/genética , Proteínas de Unión al ADN/metabolismo , Síndrome MELAS/patología , Mitocondrias/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción Activadores/metabolismo , Autofagia/genética , Fraccionamiento Celular , Respiración de la Célula/genética , Proteínas de Unión al ADN/genética , Técnicas de Inactivación de Genes , Células HEK293 , Humanos , Síndrome MELAS/genética , Mitocondrias/genética , Mutación , Oxígeno/metabolismo , Factores de Transcripción/genética , Respuesta de Proteína Desplegada/genética
19.
J Cell Mol Med ; 26(11): 3290-3293, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35587004

RESUMEN

Butyrate is a short-chain fatty acid that is produced by commensal microbes within the intestinal microbiome through fermentation of dietary fibre. Microbial-derived butyrate has been shown to promote immunologic and metabolic homeostasis, in part through its beneficial effects on mitochondrial function, and thus has been proposed as a possible anti-inflammatory therapy. We tested the hypothesis that butyrate could mitigate the decrease in mitochondrial respiration in immune cells under septic conditions as a preliminary step towards better understanding the potential for butyrate as a novel therapy in sepsis. Mitochondrial respiration and content (measured as citrate synthase activity) were compared within four Epstein-Barr virus-transformed lymphoblast (LB) cell lines exposed to either control media or lipopolysaccharide (LPS) 100 ng/ml. Both co-incubation of LBs with LPS + butyrate and treatment with butyrate after LPS stimulation reversed the decrease in mitochondrial respiration observed in LBs exposed to LPS without butyrate. Neither LPS nor butyrate led to significant changes in citrate synthase activity. The preliminary findings support further investigation of a potential mitochondrial-based mechanism through which butyrate may help to mitigate the immuno-inflammatory response in sepsis.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Sepsis , Ácido Butírico/farmacología , Citrato (si)-Sintasa , Herpesvirus Humano 4/metabolismo , Humanos , Lipopolisacáridos/metabolismo , Mitocondrias/metabolismo , Sepsis/tratamiento farmacológico
20.
Anal Chem ; 94(19): 6930-6938, 2022 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35502898

RESUMEN

We demonstrate a fast and easy-to-use three-dimensional printed microfluidic platform for mitochondria isolation from cell and tissue lysates based on inertial microfluidics. We present and quantify the quality of the isolated mitochondria by measuring the respiration rate under various conditions. We demonstrate that the technology produces vital mitochondria of equal quality to traditional, but more burdensome, differential centrifugation. We anticipate that the availability of improved tools for studies of bioenergetics to the broader biological community will enable these and other links to be explored in more meaningful ways, leading to further understanding of the links between energy, health, and disease.


Asunto(s)
Microfluídica , Mitocondrias , Centrifugación , Metabolismo Energético , Tecnología
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