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1.
Cells ; 8(4)2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027297

RESUMO

Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization.


Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , DNA Mitocondrial/fisiologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , /fisiologia , Mutação
2.
G3 (Bethesda) ; 9(4): 1175-1188, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30745378

RESUMO

Mitochondrial DNA (mtDNA) has been one of the most extensively studied molecules in ecological, evolutionary and clinical genetics. In its early application in evolutionary genetics, mtDNA was assumed to be a selectively neutral marker conferring negligible fitness consequences for its host. However, this dogma has been overturned in recent years due to now extensive evidence for non-neutral evolutionary dynamics. Since mtDNA proteins physically interact with nuclear proteins to provide the mitochondrial machinery for aerobic ATP production, among other cell functions, co-variation of the respective genes is predicted to affect organismal fitness. To test this hypothesis we used an mtDNA-nuclear DNA introgression model in Drosophila melanogaster to test the fitness of genotypes in perturbation-reperturbation population cages and in a non-competitive assay for female fecundity. Genotypes consisted of both conspecific and heterospecific mtDNA-nDNA constructs, with either D. melanogaster or D. simulans mtDNAs on two alternative D. melanogaster nuclear backgrounds, to investigate mitonuclear genetic interactions (G x G effects). We found considerable variation between nuclear genetic backgrounds on the selection of mtDNA haplotypes. In addition, there was variation in the selection on mtDNAs pre- and post- reperturbation, demonstrating overall poor repeatability of selection. There was a strong influence of nuclear background on non-competitive fecundity across all the mtDNA species types. In only one of the four cage types did we see a significant fecundity effect between genotypes that could help explain the respective change in genotype frequency over generational time. We discuss these results in the context of G x G interactions and the possible influence of stochastic environments on mtDNA-nDNA selection.


Assuntos
DNA Mitocondrial/química , Drosophila melanogaster/genética , Animais , DNA Mitocondrial/fisiologia , Drosophila melanogaster/fisiologia , Evolução Molecular , Feminino , Fertilidade , Genótipo , Haplótipos , Masculino
3.
Hum Mol Genet ; 28(7): 1090-1099, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496414

RESUMO

TWINKLE is the helicase involved in replication and maintenance of mitochondrial DNA (mtDNA) in mammalian cells. Structurally, TWINKLE is closely related to the bacteriophage T7 gp4 protein and comprises a helicase and primase domain joined by a flexible linker region. Mutations in and around this linker region are responsible for autosomal dominant progressive external ophthalmoplegia (adPEO), a neuromuscular disorder associated with deletions in mtDNA. The underlying molecular basis of adPEO-causing mutations remains unclear, but defects in TWINKLE oligomerization are thought to play a major role. In this study, we have characterized these disease variants by single-particle electron microscopy and can link the diminished activities of the TWINKLE variants to altered oligomeric properties. Our results suggest that the mutations can be divided into those that (i) destroy the flexibility of the linker region, (ii) inhibit ring closure and (iii) change the number of subunits within a helicase ring. Furthermore, we demonstrate that wild-type TWINKLE undergoes large-scale conformational changes upon nucleoside triphosphate binding and that this ability is lost in the disease-causing variants. This represents a substantial advancement in the understanding of the molecular basis of adPEO and related pathologies and may aid in the development of future therapeutic strategies.


Assuntos
DNA Helicases/genética , DNA Helicases/ultraestrutura , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/ultraestrutura , Oftalmoplegia Externa Progressiva Crônica/genética , Sequência de Aminoácidos , DNA Primase , DNA Mitocondrial/genética , DNA Mitocondrial/fisiologia , Humanos , Microscopia Eletrônica/métodos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mutação/genética , Domínios Proteicos/genética
4.
Clin Neurophysiol ; 129(8): 1618-1623, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29890373

RESUMO

OBJECTIVE: Polyneuropathy in mitochondrial diseases (MDs) is relatively common and widely investigated, but few data are instead reported about small fibres involvement. METHODS: In order to investigate the involvement of small fibres in MDs we performed extensive neurophysiological test (nerve conduction studies; sympathetic skin response; sudoscan) in 27 patients with genetic diagnosis of MD (7 m.3243A > G; 4 m.8344A > G; 9 single mtDNA deletion; 7 multiple mtDNA deletions). RESULTS: NCS showed a polyneuropathy in 11/27 cases (41%). The incidence was very high in POLG1 (100%), m.8344A > G (75%) and m.3243A > G (43%), while only 11% of patients with single deletion had evidence of large fibres involvement. Sympathetic skin response was abnormal only in three patients (one progressive external ophthalmoplegia with single mtDNA deletion; one patient with m.3243A > G mutation; one patient with POLG1 mutation). Sudoscan revealed the presence of an autonomic small fibres dysfunction in 9/27 cases (33%), most of them (7/9) carrying a single mtDNA deletion. Sudoscan data were also confirmed in a sub-group of patients by laser evoked potentials study. Considering only patients with single mtDNA deletion 7/9 (78%) showed abnormal results at sudoscan. CONCLUSIONS: Small fibre neuropathy is another feature to investigate in mitochondrial diseases and seems specifically associated with the presence of single mtDNA deletion. SIGNIFICANCE: The correct identification through specific neurophysiological tests of small fibres involvement in MDs represents another tile in this challenging diagnosis.


Assuntos
DNA Mitocondrial/fisiologia , Potenciais Evocados por Laser/fisiologia , Doenças Mitocondriais/fisiopatologia , Neuropatia de Pequenas Fibras/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Estudos Prospectivos , Neuropatia de Pequenas Fibras/diagnóstico , Neuropatia de Pequenas Fibras/genética
5.
PLoS Pathog ; 14(5): e1007065, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29851986

RESUMO

Chagasic cardiomyopathy is caused by Trypanosoma cruzi infection. Poly(ADP-ribose) polymerase 1 (PARP1) is known for its function in nuclear DNA repair. In this study, we have employed genetic deletion and chemical inhibition approaches to determine the role of PARP1 in maintaining mtDNA dependent mitochondrial function in Chagas disease. Our data show that expression of PARP1 and protein PARylation were increased by >2-fold and >16-fold, respectively, in the cytosolic, nuclear, and mitochondrial fractions of the human cardiac myocytes and the myocardium of wildtype (WT) mice chronically infected with T. cruzi. The nuclear and cytosolic PARP1/PAR did not interfere with the transcription and translation of the components of the mtDNA replisome machinery in infected cardiomyocytes and chagasic murine myocardium. However, PARP1 binding to Polymerase γ and mtDNA in mitochondria were increased, and associated with a loss in mtDNA content, mtDNA-encoded gene expression, and oxidative phosphorylation (OXPHOS) capacity, and an increase in mitochondrial ROS production in cells and heart of WT mice infected with T. cruzi. Subsequently, an increase in oxidative stress, and cardiac collagen deposition, and a decline in LV function was noted in chagasic mice. Genetic deletion of PARP1 or treatment with selective inhibitor of PARP1 (PJ34) improved the mtDNA content, mitochondrial function, and oxidant/antioxidant balance in human cardiomyocytes and chronically infected mice. Further, PARP1 inhibition was beneficial in preserving the cardiac structure and left ventricular function in chagasic mice. We conclude that PARP1 overexpression is associated with a decline in Pol γ-dependent maintenance of mtDNA content, mtDNA-encoded gene expression, and mitochondrial respiratory function, and subsequently contributes to an increase in mtROS and oxidative stress in chagasic myocardium. Inhibition of mitochondrial PARP1/PAR offers a novel therapy in preserving the mitochondrial and LV function in chronic Chagas disease.


Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Polimerase do DNA Mitocondrial/genética , DNA Mitocondrial/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Antioxidantes/metabolismo , Células Cultivadas , Cardiomiopatia Chagásica/genética , Imunoprecipitação da Cromatina , DNA de Protozoário/fisiologia , Células HeLa , Coração/fisiologia , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Células Musculares/metabolismo , Miócitos Cardíacos/citologia , Estresse Oxidativo , Fenantrenos/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/genética , Função Ventricular Esquerda/fisiologia
6.
Sci Rep ; 8(1): 7350, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743484

RESUMO

Ischemia-reperfusion (I/R) injury is a challenging clinical problem, especially injuries involving the gastrointestinal tract. Mitochondrial DNA (mtDNA) is released upon cell death and stress, and can induce the inflammatory response. We aimed to investigate the role of mtDNA in the pathogenesis of intestinal I/R. Intestinal I/R model was established with clamping of the superior mesenteric artery, and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury. Using in vitro models, H/R up-regulated oxidative stress, disrupted mitochondrial activity and the mitochondrial membrane potential, induced apoptosis and elevated the mtDNA levels in the supernatant of intestinal epithelial cells, and the co-culture of mtDNA with human primary dendritic cells significantly elevated TLR9-MyD88 expression and enhanced the production of inflammatory cytokines and chemokines. MtDNA was also released in a mouse model of intestinal I/R and was associated with the increased secretion of inflammatory cytokines and increased gut barrier injury compared with that of the sham group. We concluded that mtDNA contributes to I/R injury and may serve as a biomarker of intestinal I/R. We further suggest that oxidized mtDNA originated from IECs during intestinal I/R exacerbates the acute proinflammatory process by eliciting the production of proinflammatory cytokines and chemokines.


Assuntos
DNA Mitocondrial/fisiologia , Mucosa Intestinal/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose , Linhagem Celular , China , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Trato Gastrointestinal/metabolismo , Humanos , Inflamação/metabolismo , Intestinos/imunologia , Intestinos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Estresse Oxidativo , Reperfusão , Traumatismo por Reperfusão/genética
7.
Eur J Epidemiol ; 33(5): 485-495, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29619669

RESUMO

Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.


Assuntos
Adiposidade/fisiologia , Índice de Massa Corporal , Variações do Número de Cópias de DNA/fisiologia , DNA Mitocondrial/fisiologia , Leucócitos/fisiologia , Telômero/fisiologia , Adolescente , Adulto , Envelhecimento/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos , Adulto Jovem
8.
Biochem J ; 475(5): 839-852, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29511093

RESUMO

Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection - termed sterile inflammation - is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP-AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases.


Assuntos
Doenças Cardiovasculares/genética , DNA Mitocondrial/fisiologia , Mediadores da Inflamação/metabolismo , Inflamação/genética , Animais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Humanos , Inflamação/complicações
9.
Biogerontology ; 19(3-4): 189-208, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29488130

RESUMO

In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to slow down or even prevent these diseases and provide opportunities for healthy ageing; additionally, we all want to live longer. Ageing is a consequence of the interaction between processes that occur over time and genetics interacting with various disease states and an individual's lifestyle. There are several hallmarks of ageing that are generally accepted, but neither of the theories appears to be fully satisfactory. The focus of this article is on two theories of ageing: telomere shortening and mitochondrial DNA (mtDNA) alterations and dysfunction. We discuss characteristic molecular features such as mitochondrial haplogroups, telomere length, mtDNA copy number and heteroplasmy, and how all these traits come together in the ageing population. The recent evidence shows the existence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans' ageing. However, this relationship is still not completely understood, which is why it needs more attention.


Assuntos
Envelhecimento/fisiologia , Dano ao DNA , Mitocôndrias/genética , Encurtamento do Telômero , DNA Mitocondrial/fisiologia , Humanos
10.
Nat Rev Mol Cell Biol ; 19(2): 77-92, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28792006

RESUMO

Mitochondrial diseases affect one in 2,000 individuals; they can present at any age and they can manifest in any organ. How defects in mitochondria can cause such a diverse range of human diseases remains poorly understood. Insight into this diversity is emerging from recent research that investigated defects in mitochondrial protein synthesis and mitochondrial DNA maintenance, which showed that many cell-specific stress responses are induced in response to mitochondrial dysfunction. Studying the molecular regulation of these stress responses might increase our understanding of the pathogenesis and variability of human mitochondrial diseases.


Assuntos
Mitocôndrias/fisiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Animais , DNA Mitocondrial/genética , DNA Mitocondrial/fisiologia , Humanos , Organelas/patologia , Organelas/fisiologia , Estresse Oxidativo
11.
Acta Physiol (Oxf) ; 222(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29178461

RESUMO

The Guardian of the Genome p53 has been established as a potent tumour suppressor. However, culminating from seminal findings in rodents more than a decade ago, several studies have demonstrated that p53 is required to maintain basal mitochondrial function [ie, respiration and reactive oxygen species (ROS) homeostasis]. Specifically, via its role(s) as a tumour suppressor, p53 intimately surveys cellular DNA damage, in particular mitochondrial DNA (mtDNA), to ensure that the mitochondrial network is carefully monitored and cell viability is upheld, because aberrant mtDNA damage leads to apoptosis and widespread cellular perturbations. Indeed, data from rodents and humans have demonstrated that p53 forms an integral component of the exercise-induced signal transduction network regulating skeletal muscle mitochondrial remodelling. In response to exercise-induced disruptions to cellular homeostasis that have the potential to harm mtDNA (eg, contraction-stimulated ROS emissions), appropriate p53-regulated, mitochondrial turnover responses prevail to protect the genome and ultimately facilitate a shift from aerobic glycolysis to oxidative phosphorylation, adaptations critical for endurance-based exercise that are commensurate with p53's role as a tumour suppressor. Despite these observations, several discrepancies exist between rodent and human studies pinpointing p53 subcellular trafficking from nuclear-to-mitochondrial compartments following acute exercise. Such interspecies differences in p53 activity and the plausible p53-mediated adaptations to chronic exercise training will be discussed herein.


Assuntos
Exercício/fisiologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , DNA Mitocondrial/fisiologia , Humanos , Biogênese de Organelas , Transporte Proteico/fisiologia , Especificidade da Espécie
12.
Metabolism ; 81: 97-112, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29162500

RESUMO

Immunometabolism aims to define the role of intermediary metabolism in immune cell function, with bioenergetics and the mitochondria recently taking center stage. To date, the medical literature on mitochondria and immune function extols the virtues of mouse models in exploring this biologic intersection. While the laboratory mouse has become a standard for studying mammalian biology, this model comprises part of a comprehensive approach. Humans, with their broad array of inherited phenotypes, serve as a starting point for studying immunometabolism; specifically, patients with mitochondrial disease. Using this top-down approach, the mouse as a model organism facilitates further exploration of the consequences of mutations involved in mitochondrial maintenance and function. In this review, we will discuss the emerging phenotype of immune dysfunction in mitochondrial disease as a model for understanding the role of the mitochondria in immune function in available mouse models.


Assuntos
Sistema Imunitário/fisiologia , Doenças Mitocondriais/imunologia , Animais , Cálcio/metabolismo , Fusão Celular , DNA Mitocondrial/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos , Fosforilação Oxidativa
13.
Eur Heart J ; 38(46): 3443-3448, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29020391

RESUMO

Aims: Sudden cardiac death (SCD) is a major public health burden. Mitochondrial dysfunction has been implicated in a wide range of cardiovascular diseases including cardiomyopathy, heart failure, and arrhythmias, but it is unknown if it also contributes to SCD risk. We sought to examine the prospective association between mtDNA copy number (mtDNA-CN), a surrogate marker of mitochondrial function, and SCD risk. Methods and results: We measured baseline mtDNA-CN in 11 093 participants from the Atherosclerosis Risk in Communities (ARIC) study. mtDNA copy number was calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) on the Affymetrix Genome-Wide Human SNP Array 6.0. Sudden cardiac death was defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual without evidence of a non-cardiac cause of cardiac arrest. Sudden cardiac death cases were reviewed and adjudicated by an expert committee. During a median follow-up of 20.4 years, we observed 361 SCD cases. After adjusting for age, race, sex, and centre, the hazard ratio for SCD comparing the 1st to the 5th quintiles of mtDNA-CN was 2.24 (95% confidence interval 1.58-3.19; P-trend <0.001). When further adjusting for traditional cardiovascular disease risk factors, prevalent coronary heart disease, heart rate, QT interval, and QRS duration, the association remained statistically significant. Spline regression models showed that the association was approximately linear over the range of mtDNA-CN values. No apparent interaction by race or by sex was detected. Conclusion: In this community-based prospective study, mtDNA-CN in peripheral blood was inversely associated with the risk of SCD.


Assuntos
Variações do Número de Cópias de DNA/fisiologia , DNA Mitocondrial/fisiologia , Morte Súbita Cardíaca/etiologia , Doença da Artéria Coronariana/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
14.
Oncogene ; 36(31): 4393-4404, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28368421

RESUMO

By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPRmt). The UPRmt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPRmt, we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPRmt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.


Assuntos
DNA Mitocondrial/fisiologia , Metástase Neoplásica , Sirtuína 3/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Proteína Forkhead Box O3/fisiologia , Humanos , Mitocôndrias/patologia , Superóxido Dismutase/fisiologia
15.
FASEB J ; 31(6): 2520-2532, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28258190

RESUMO

Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic lungs and thereby augments AEC mtDNA damage and apoptosis. Human lungs were assessed by using immunohistochemistry for SIRT3 activity via acetylated MnSODK68 Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis via ELISA. Pulmonary fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice (Sirt3-/- ) by using fibrosis scoring and lung collagen levels. Idiopathic pulmonary fibrosis lung alveolar type II cells have increased MnSODK68 acetylation compared with controls. Asbestos and H2O2 diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68 SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341 acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced lung fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified in Sirt3-/- animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and lung fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.


Assuntos
Células Epiteliais Alveolares/patologia , Apoptose/fisiologia , DNA Mitocondrial/fisiologia , Fibrose Pulmonar/etiologia , Sirtuína 3/metabolismo , Células A549 , Animais , Antibióticos Antineoplásicos/toxicidade , Asbestos/toxicidade , Bleomicina/toxicidade , Dano ao DNA , Humanos , Camundongos , Camundongos Knockout , Oxidantes/toxicidade , Fibrose Pulmonar/metabolismo , Sirtuína 3/genética
16.
Nat Microbiol ; 2: 17037, 2017 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-28346446

RESUMO

During the last few decades, the global incidence of dengue virus (DENV) has increased dramatically, and it is now endemic in more than 100 countries. To establish a productive infection in humans, DENV uses different strategies to inhibit or avoid the host innate immune system. Several DENV proteins have been shown to strategically target crucial components of the type I interferon system. Here, we report that the DENV NS2B protease cofactor targets the DNA sensor cyclic GMP-AMP synthase (cGAS) for lysosomal degradation to avoid the detection of mitochondrial DNA during infection. Such degradation subsequently results in the inhibition of type I interferon production in the infected cell. Our data demonstrate a mechanism by which cGAS senses cellular damage upon DENV infection.


Assuntos
DNA Mitocondrial/fisiologia , Vírus da Dengue/genética , Interações Hospedeiro-Patógeno , Nucleotidiltransferases/metabolismo , Proteínas não Estruturais Virais/metabolismo , DNA Mitocondrial/genética , Células Dendríticas/virologia , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/química , Vírus da Dengue/enzimologia , Vírus da Dengue/imunologia , Células HEK293 , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/deficiência , Nucleotidiltransferases/genética , Nucleotidiltransferases/imunologia , Transdução de Sinais , Proteínas não Estruturais Virais/genética
17.
Ageing Res Rev ; 33: 89-104, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27143693

RESUMO

As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.


Assuntos
Envelhecimento , DNA Mitocondrial , Mitocôndrias/genética , Mutagênese/fisiologia , Envelhecimento/genética , Envelhecimento/metabolismo , Replicação do DNA , DNA Mitocondrial/genética , DNA Mitocondrial/fisiologia , Genes Mitocondriais/genética , Humanos , Mutação , Espécies Reativas de Oxigênio/metabolismo
18.
Reprod Fertil Dev ; 30(1): 118-139, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29539308

RESUMO

In mammalian species, the mitochondrial genome is between 16.2 and 16.7kb in size and encodes key proteins associated with the cell's major energy-generating apparatus, the electron transfer chain. The maternally inherited mitochondrial genome has, until recently, been thought to be only involved in the production of energy. In this review, we analyse how the mitochondrial genome influences the developing embryo and cellular differentiation, as well as fetal and offspring health and wellbeing. We make specific reference to two assisted reproductive technologies, namely mitochondrial supplementation and somatic cell nuclear transfer, and how modulating the mitochondrial content in the oocyte influences embryo viability and the potential to generate enhanced offspring for livestock production purposes. We also explain why it is important to ensure that the transmission of only one population of mitochondrial (mt) DNA is maintained through to the offspring and why two populations of genetically distinct mitochondrial genomes could be deleterious. Finally, we explain how mtDNA influences chromosomal gene expression patterns in developing embryos and cells primarily by modulating DNA methylation patterns through factors associated with the citric acid cycle. These factors can then modulate the ten-eleven translocation (TET) pathway, which, in turn, determines whether a cell is in a more or less DNA methylated state.


Assuntos
DNA Mitocondrial/fisiologia , Fertilidade/genética , Genoma Mitocondrial/fisiologia , Animais , Metilação de DNA/fisiologia , Desenvolvimento Embrionário/fisiologia , Humanos , Mamíferos , Técnicas de Reprodução Assistida/tendências , Técnicas de Reprodução Assistida/veterinária
19.
Mediators Inflamm ; 2017: 2309034, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29445253

RESUMO

A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondria activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells. We discuss the potential role of several of SA-mitomiRs (i.e., let-7b, miR-1, miR-130a-3p, miR-133a, miR-146a-5p, miR-181c-5p, and miR-378-5p), using miR-146a as a proof-of-principle model. Finally, we propose a comprehensive, metabolic, and epigenetic view of the senescence process, in order to amplify the range of possible approaches to target inflammaging, with the ultimate goal of decelerating the aging rate, postponing or blunting the development of age-related diseases.


Assuntos
Senescência Celular , Inflamação/etiologia , MicroRNAs/fisiologia , Mitocôndrias/fisiologia , DNA Mitocondrial/fisiologia , Humanos , NF-kappa B/fisiologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
20.
Physiol Res ; 65(Supplementum 5): S519-S531, 2016 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-28006935

RESUMO

Aging is a multifactorial process influenced by genetic factors, nutrition, and lifestyle. According to mitochondrial theory of aging, mitochondrial dysfunction is widely considered a major contributor to age-related processes. Mitochondria are both the main source and targets of detrimental reactions initiated in association with age-dependent deterioration of the cellular functions. Reactions leading to increased reactive oxygen species generation, mtDNA mutations, and oxidation of mitochondrial proteins result in subsequent induction of apoptotic events, impaired oxidative phosphorylation capacity, mitochondrial dynamics, biogenesis and autophagy. This review summarizes the major changes of mitochondria related to aging, with emphasis on mitochondrial DNA mutations, the role of the reactive oxygen species, and structural and functional changes of mitochondria.


Assuntos
Envelhecimento/fisiologia , DNA Mitocondrial/fisiologia , Mitocôndrias/fisiologia , Animais , Autofagia/fisiologia , Humanos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
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