Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 140.598
Filtrar
1.
Cell Biochem Funct ; 42(4): e4025, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845083

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Metabolic and mitochondrial dysregulation are critical causal factors in the pathogenesis and progression of RA. Mitochondrial dysfunction include abnormal energy metabolism, and excessive production of reactive oxygen species (ROS). This study aimed to investigate the adenosine triphosphate (ATP), mitochondrial membrane potential (ΔΨm), ROS, and mRNA expression level of ROMO1 (as ROS modulator) and OMA1 (as regulator mitochondrial dynamics) of peripheral blood mononuclear cells (PBMC) in RA patients. The study participants were 50 patients with RA and 50 sex- and age-matched healthy volunteers. PBMC of all participant were isolated by Ficoll-Paque. Alteration in ΔΨm and cellular ROS were measured using flow cytometry, ATP level was also assessed via luminometry, and ROMO1 and OMA1 mRNA expression via qRT-PCR assay. A significant decrease in ATP (p = .005) and ΔΨm (p < .001) was observed in the PBMC of RA compared to control. The ROS levels were significantly higher in the PBMC of RA compared to the control (p < .001). ROMO1 and OMA1 mRNA expression was also significantly increased in RA patients compared to control (p < .001). The decrease in ATP is strongly associated with ROS increasing in PBMC of RA patients, denoting an inverse and negative relationship between ATP and ROS production. Also, a decrease in ΔΨm was observed. It seems that in line with mitochondrial dysfunction in PBMC, increased expression of ROMO1 and OMA1 genes could also be involved in the development of RA.


Assuntos
Artrite Reumatoide , Leucócitos Mononucleares , Mitocôndrias , Espécies Reativas de Oxigênio , Humanos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Leucócitos Mononucleares/metabolismo , Feminino , Masculino , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Pessoa de Meia-Idade , Biomarcadores/metabolismo , Biomarcadores/sangue , Trifosfato de Adenosina/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Adulto , Potencial da Membrana Mitocondrial , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética
2.
Anim Sci J ; 95(1): e13966, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38845341

RESUMO

Prolonged exposure of bisphenol A (BPA) has adverse effects on in vitro maturation (IVM) of oocytes, but treatment with tauroursodeoxycholic acid (TUDCA) can improve the IVM and development of embryos. The purpose of this study was to investigate the effects of BPA and both BPA and TUDCA on IVM and parthenogenetic development of embryos. The results showed that BPA treatment adverse effects on the cumulus expansion index, survival rate, polar body rate, mitochondrial distribution of the oocytes after maturation culture, and that it also decreased the cleavage rate and blastocyst rate of embryos after parthenogenetic develpoment. In addition, BPA treatment upregulated expression of genes related to endoplasmic reticulum stress and apoptosis and increased the intracellular reactive oxygen species (ROS) level, while it decreased expression of genes related to cumulus expansion. However, the supplementation of TUDCA relieved these adverse effects of BPA except polar body rate, blastocyst rate, and expression of BCL2 and PTGS1. In conclusion, the supplementation of TUDCA can partly attenuate the negative effects of BPA on IVM and parthenogenetic development of embryos, possibly by modification of the expression of genes related to endoplasmic reticulum stress, apoptosis and cumulus expansion, intracellular ROS level, and mitochondrial distribution.


Assuntos
Apoptose , Compostos Benzidrílicos , Desenvolvimento Embrionário , Estresse do Retículo Endoplasmático , Técnicas de Maturação in Vitro de Oócitos , Oócitos , Partenogênese , Fenóis , Espécies Reativas de Oxigênio , Ácido Tauroquenodesoxicólico , Animais , Fenóis/toxicidade , Ácido Tauroquenodesoxicólico/farmacologia , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Suínos/embriologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Blastocisto/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos
3.
FASEB J ; 38(11): e23718, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38847487

RESUMO

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA-binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.


Assuntos
Estrogênios , Camundongos Endogâmicos mdx , Músculo Esquelético , Proteínas de Ligação a RNA , Animais , Feminino , Camundongos , Estrogênios/metabolismo , Estrogênios/farmacologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/genética , Camundongos Endogâmicos C57BL , Ovariectomia , Mitocôndrias/metabolismo , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos
4.
Technol Cancer Res Treat ; 23: 15330338241258570, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38832431

RESUMO

Background: Colon adenocarcinoma (COAD) has increasing incidence and is one of the most common malignant tumors. The mitochondria involved in cell energy metabolism, oxygen free radical generation, and cell apoptosis play important roles in tumorigenesis and progression. The relationship between mitochondrial genes and COAD remains largely unknown. Methods: COAD data including 512 samples were set out from the UCSC Xena database. The nuclear mitochondrial-related genes (NMRGs)-related risk prognostic model and prognostic nomogram were constructed, and NMRGs-related gene mutation and the immune environment were analyzed using bioinformatics methods. Then, a liver metastasis model of colorectal cancer was constructed and protein expression was detected using Western blot assay. Results: A prognostic model for COAD was constructed. Comparing the prognostic model dataset and the validation dataset showed considerable correlation in both risk grouping and prognosis. Based on the risk score (RS) model, the samples of the prognostic dataset were divided into high risk group and low risk group. Moreover, pathologic N and T stage and tumor recurrence in the two risk groups were significantly different. The four prognostic factors, including age and pathologic T stage in the nomogram survival model also showed excellent predictive performance. An optimal combination of nine differentially expressed NMRGs was finally obtained, including LARS2, PARS2, ETHE1, LRPPRC, TMEM70, AARS2, ACAD9, VARS2, and ATP8A2. The high-RS group had more inflamed immune features, including T and CD4+ memory cell activation. Besides, mitochondria-associated LRPPRC and LARS2 expression levels were increased in vivo xenograft construction and liver metastases assays. Conclusion: This study established a comprehensive prognostic model for COAD, incorporating nine genes associated with nuclear-mitochondrial functions. This model demonstrates superior predictive performance across four prognostic factors: age, pathological T stage, tumor recurrence, and overall prognosis. It is anticipated to be an effective model for enhancing the prognosis and treatment of COAD.


Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/mortalidade , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Camundongos , Animais , Biomarcadores Tumorais/genética , Nomogramas , Biologia Computacional/métodos , Genes Mitocondriais , Modelos Animais de Doenças , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Perfilação da Expressão Gênica , Estadiamento de Neoplasias , Masculino , Bases de Dados Genéticas , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Feminino
5.
Acta Neuropathol Commun ; 12(1): 88, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840253

RESUMO

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.


Assuntos
Modelos Animais de Doenças , Doença de Huntington , Imageamento Tridimensional , Mitocôndrias , Animais , Doença de Huntington/patologia , Doença de Huntington/genética , Doença de Huntington/metabolismo , Mitocôndrias/ultraestrutura , Mitocôndrias/patologia , Mitocôndrias/metabolismo , Imageamento Tridimensional/métodos , Camundongos , Camundongos Transgênicos , Encéfalo/patologia , Encéfalo/ultraestrutura , Encéfalo/metabolismo , Microscopia Eletrônica/métodos , Masculino , Neurônios/patologia , Neurônios/ultraestrutura , Neurônios/metabolismo
6.
Front Immunol ; 15: 1411132, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840928

RESUMO

Background: Cervical cancer remains a significant gynecologic malignancy in both China and the United States, posing a substantial threat to women's lives and health due to its high morbidity and mortality rates. Altered energy metabolism and dysregulated mitochondrial function play crucial roles in the development, growth, metastasis, and recurrence of malignant tumors. In this study, we aimed to predict prognosis and assess efficacy of anti-tumor therapy in cervical cancer patients based on differential genes associated with mitochondrial metabolism. Methods: Transcriptomic data and clinical profiles of cervical cancer patients were retrieved from the TCGA and GEO databases. Differential gene-related cellular pathways were identified through GO, KEGG, and GSEA analyses. Prognostic indices were constructed using LASSO regression analysis. Immune cell infiltration was assessed using CIBERSORT and ssGSEA, and the correlation between immune checkpoint inhibitor genes and differential genes was examined. Tumor mutation load (TMB) and its association with prognostic indices were analyzed using nucleotide variant data from the TCGA database. Patient response to immunotherapy and sensitivity to antitumor drugs were determined using the TIDE algorithm and the oncoPredic algorithm, respectively. Results: A prognostic index based on metabolism-related differential genes was developed to predict the clinical outcome of cervical cancer patients, enabling their classification into two distinct subtypes. The prognostic index emerged as an independent risk factor for unfavorable prognosis. The high-index group exhibited a significantly worse overall prognosis, along with elevated tumor mutation burden (TMB), increased immune cell infiltration, and lower TIDE scores, indicating a potential benefit from immunotherapy. Conversely, the low-index group demonstrated increased sensitivity to metabolism-related antitumor agents, specifically multikinase inhibitors. Conclusion: The aim of this study was to develop a prognostic index based on differential genes associated with mitochondrial metabolism, which could be used to predict cervical cancer patients' prognoses. When combined with TIDE and TMB analyses, this prognostic index offers insights into the immune cell infiltration landscape, as well as the potential efficacy of immunotherapy and targeted therapy. Our analysis suggests that the Iron-Sulfur Cluster Assembly Enzyme (ISCU) gene holds promise as a biomarker for cervical cancer immunotherapy.


Assuntos
Biomarcadores Tumorais , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/mortalidade , Feminino , Prognóstico , Biomarcadores Tumorais/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Mitocôndrias/metabolismo , Mitocôndrias/genética , Metabolismo Energético/genética , Bases de Dados Genéticas , Pessoa de Meia-Idade , Mutação , Perfilação da Expressão Gênica
7.
PLoS One ; 19(6): e0300602, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38829894

RESUMO

OBJECTIVES: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. DESIGN: Prospective cohort study. SETTING: Measurements were performed in Leiden University Medical Center, the Netherlands. PARTICIPANTS: Healthy volunteers enrolled from July to September 2020. INTERVENTIONS: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. PRIMARY AND SECONDARY OUTCOME MEASURES: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. RESULTS: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). CONCLUSIONS: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. TRIAL REGISTRATION: ClinicalTrials.gov with trial number NCT04626661.


Assuntos
Voluntários Saudáveis , Oxigênio , Humanos , Masculino , Feminino , Adulto , Oxigênio/metabolismo , Estudos Prospectivos , Mitocôndrias/metabolismo , Pessoa de Meia-Idade , Ácido Aminolevulínico/administração & dosagem , Consumo de Oxigênio , Adulto Jovem , Países Baixos
8.
Nat Commun ; 15(1): 4700, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38830851

RESUMO

BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.


Assuntos
Apoptose , Membranas Mitocondriais , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2 , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Humanos , Membranas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Mitocôndrias/metabolismo , Linhagem Celular Tumoral , Ácidos Graxos Insaturados/metabolismo , Ácidos Graxos Insaturados/farmacologia , Animais
9.
Methods Mol Biol ; 2792: 51-75, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38861078

RESUMO

Mitochondrial dihydrolipoamide dehydrogenase (mtLPD1) is a central enzyme in primary carbon metabolism, since its function is required to drive four multienzymes involved in photorespiration, the tricarboxylic acid (TCA) cycle, and the degradation of branched-chain amino acids. However, in illuminated, photosynthesizing tissue a vast amount of mtLPD1 is necessary for glycine decarboxylase (GDC), the key enzyme of photorespiration. In light of the shared role, the functional characterization of mtLPD1 is necessary to understand how the three pathways might interact under different environmental scenarios. This includes the determination of the biochemical properties and all potential regulatory mechanisms, respectively. With regards to the latter, regulation can occur through multiple levels including effector molecules, cofactor availability, or posttranslational modifications (PTM), which in turn decrease or increase the activity of each enzymatic reaction. Gaining a comprehensive overview on all these aspects would ultimately facilitate the interpretation of the metabolic interplay of the pathways within the whole subcellular network or even function as a proof of concept for genetic engineering approaches. Here, we describe the typical workflow how to clone, express, and purify plant mtLPD1 for biochemical characterization and how to analyze potential redox regulatory mechanisms in vitro and in planta.


Assuntos
Di-Hidrolipoamida Desidrogenase , Oxirredução , Di-Hidrolipoamida Desidrogenase/metabolismo , Di-Hidrolipoamida Desidrogenase/genética , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/enzimologia , Arabidopsis/genética , Arabidopsis/enzimologia , Arabidopsis/metabolismo , Clonagem Molecular/métodos
10.
Drug Dev Res ; 85(4): e22221, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863387

RESUMO

Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription-quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high- and low-HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain- and loss-of-function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria-mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC.


Assuntos
Apoptose , Regulação para Baixo , Sistema de Sinalização das MAP Quinases , Mitocôndrias , Proteínas Proto-Oncogênicas c-akt , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/genética , Linhagem Celular Tumoral , Proliferação de Células , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica
11.
Cell Mol Life Sci ; 81(1): 250, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847861

RESUMO

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.


Assuntos
Retículo Endoplasmático , Mitocôndrias , Oxirredução , Transdução de Sinais , Resposta a Proteínas não Dobradas , Humanos , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Animais , Estresse do Retículo Endoplasmático
12.
J Transl Med ; 22(1): 552, 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853272

RESUMO

Acute myocardial infarction (AMI) is a serious condition that occurs when part of the heart is subjected to ischemia episodes, following partial or complete occlusion of the epicardial coronary arteries. The resulting damage to heart muscle cells have a significant impact on patient's health and quality of life. About that, recent research focused on the role of the sarcoplasmic reticulum (SR) and mitochondria in the physiopathology of AMI. Moreover, SR and mitochondria get in touch each other through multiple membrane contact sites giving rise to the subcellular region called mitochondria-associated membranes (MAMs). MAMs are essential for, but not limited to, bioenergetics and cell fate. Disruption of the architecture of these regions occurs during AMI although it is still unclear the cause-consequence connection and a complete overview of the pathological changes; for sure this concurs to further damage to heart muscle. The calcium ion (Ca2+) plays a pivotal role in the pathophysiology of AMI and its dynamic signaling between the SR and mitochondria holds significant importance. In this review, we tried to summarize and update the knowledge about the roles of these organelles in AMI from a Ca2+ signaling point of view. Accordingly, we also reported some possible cardioprotective targets which are directly or indirectly related at limiting the dysfunctions caused by the deregulation of the Ca2+ signaling.


Assuntos
Sinalização do Cálcio , Mitocôndrias , Infarto do Miocárdio , Retículo Sarcoplasmático , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Retículo Sarcoplasmático/metabolismo , Animais , Mitocôndrias/metabolismo , Cálcio/metabolismo
13.
Cell ; 187(12): 2897-2897.e1, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848671

RESUMO

Resmetirom is an oral selective THR-ß agonist conditionally approved for the treatment of patients with noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom restores mitochondrial and hepatic metabolic function; reduces atherogenic lipids; improves hepatic steatosis, inflammation, and fibrosis; and has no significant effect on THR-α. To view this Bench to Bedside, open or download the PDF.


Assuntos
Cirrose Hepática , Piridazinas , Uracila , Animais , Humanos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Piridazinas/uso terapêutico , Uracila/análogos & derivados
14.
Acta Neuropathol Commun ; 12(1): 90, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851733

RESUMO

Mitochondrial dysfunctions are key features of Alzheimer's disease (AD). The occurrence of these disturbances in the peripheral cells of AD patients and their potential correlation with disease progression are underinvestigated. We studied mitochondrial structure, function and mitophagy in fibroblasts from healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, namely, (i) Mini-Mental State Examination (MMSE) and (ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB), and with (iii) amyloid beta (Aß) plaque burden (PiB-PET imaging) and (iv) the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). We revealed alterations in mitochondrial structure as well as specific mitochondrial dysfunction signatures in AD-MCI and AD-D fibroblasts and revealed that defective mitophagy and autophagy are linked to impaired lysosomal activity in AD-D fibroblasts. We reported significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. This study emphasizes the potential use of peripheral cells for investigating AD pathophysiology.


Assuntos
Doença de Alzheimer , Fibroblastos , Mitocôndrias , Mitofagia , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Fibroblastos/patologia , Fibroblastos/metabolismo , Idoso , Feminino , Mitocôndrias/patologia , Mitocôndrias/metabolismo , Masculino , Mitofagia/fisiologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Autofagia/fisiologia
15.
Nat Commun ; 15(1): 4915, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851747

RESUMO

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.


Assuntos
Glucose , Homeostase , Músculo Esquelético , NAD , Receptores Acoplados a Proteínas G , Animais , Músculo Esquelético/metabolismo , NAD/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Masculino , Glucose/metabolismo , Camundongos , Camundongos Knockout , Humanos , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fosforilação
16.
Front Immunol ; 15: 1396827, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855102

RESUMO

Glucocorticoids, which have long served as fundamental therapeutics for diverse inflammatory conditions, are still widely used, despite associated side effects limiting their long-term use. Among their key mediators is glucocorticoid-induced leucine zipper (GILZ), recognized for its anti-inflammatory and immunosuppressive properties. Here, we explore the immunomodulatory effects of GILZ in macrophages through transcriptomic analysis and functional assays. Bulk RNA sequencing of GILZ knockout and GILZ-overexpressing macrophages revealed significant alterations in gene expression profiles, particularly impacting pathways associated with the inflammatory response, phagocytosis, cell death, mitochondrial function, and extracellular structure organization activity. GILZ-overexpression enhances phagocytic and antibacterial activity against Salmonella typhimurium and Escherichia coli, potentially mediated by increased nitric oxide production. In addition, GILZ protects macrophages from pyroptotic cell death, as indicated by a reduced production of reactive oxygen species (ROS) in GILZ transgenic macrophages. In contrast, GILZ KO macrophages produced more ROS, suggesting a regulatory role of GILZ in ROS-dependent pathways. Additionally, GILZ overexpression leads to decreased mitochondrial respiration and heightened matrix metalloproteinase activity, suggesting its involvement in tissue remodeling processes. These findings underscore the multifaceted role of GILZ in modulating macrophage functions and its potential as a therapeutic target for inflammatory disorders, offering insights into the development of novel therapeutic strategies aimed at optimizing the benefits of glucocorticoid therapy while minimizing adverse effects.


Assuntos
Macrófagos , Mitocôndrias , Fagocitose , Piroptose , Fatores de Transcrição , Animais , Mitocôndrias/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Imunomodulação , Espécies Reativas de Oxigênio/metabolismo , Camundongos Knockout , Glucocorticoides/farmacologia , Camundongos Endogâmicos C57BL , Salmonella typhimurium/imunologia , Escherichia coli/imunologia
17.
Theranostics ; 14(8): 3282-3299, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855179

RESUMO

Rationale: Pharmacological targeting of mitochondrial ion channels is developing as a new direction in cancer therapy. The opening or closing of these channels can impact mitochondrial function and structure by interfering with intracellular ion homeostasis, thereby regulating cell fate. Nevertheless, their abnormal expression or regulation poses challenges in eliminating cancer cells, and further contributes to metastasis, recurrence, and drug resistance. Methods: We developed an engineered mitochondrial targeted delivery system with self-reinforcing potassium ion (K+) influx via amphiphilic mitochondrial targeting polymer (TMP) as carriers to co-deliver natural K+ channel agonists (Dinitrogen oxide, DZX) and artificial K+ channel molecules (5F8). Results: Using this method, DZX specifically activated natural K+ channels, whereas 5F8 assembled artificial K+ channels on the mitochondrial membrane, leading to mitochondrial K+ influx, as well as oxidative stress and activation of the mitochondrial apoptotic pathway. Conclusion: The synergistic effect of 5F8 and DZX presents greater effectiveness in killing cancer cells than DZX alone, and effectively inhibited tumor recurrence and lung metastasis following surgical resection of breast cancer tumors in animal models. This strategy innovatively integrates antihypertensive drugs with artificial ion channel molecules for the first time to effectively inhibit tumor recurrence and metastasis by disrupting intracellular ion homeostasis, which will provide a novel perspective for postoperative tumor therapy.


Assuntos
Homeostase , Mitocôndrias , Animais , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Homeostase/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Feminino , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Apoptose/efeitos dos fármacos , Potássio/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Canais Iônicos/metabolismo , Canais de Potássio/metabolismo , Camundongos Nus , Metástase Neoplásica
18.
Nat Commun ; 15(1): 4683, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824131

RESUMO

The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3'-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for this tRNA methyltransferase subcomplex for mt-RNase P cleavage activity, as well as the mechanisms of pre-tRNA 3'-cleavage and 3'-CCA addition, are still poorly understood. Here, we report cryo-EM structures that visualise four steps of mitochondrial tRNA maturation: 5' and 3' tRNA-end processing, methylation and 3'-CCA addition, and explain the defined sequential order of the tRNA processing steps. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA-end processing and 3'-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-fragile mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes. Altogether, our study provides detailed molecular insight into RNA-transcript processing and tRNA maturation in human mitochondria.


Assuntos
Mitocôndrias , RNA de Transferência , Ribonuclease P , tRNA Metiltransferases , Humanos , RNA de Transferência/metabolismo , RNA de Transferência/genética , RNA de Transferência/química , Mitocôndrias/metabolismo , Ribonuclease P/metabolismo , Ribonuclease P/genética , Ribonuclease P/química , tRNA Metiltransferases/metabolismo , tRNA Metiltransferases/genética , tRNA Metiltransferases/química , Processamento Pós-Transcricional do RNA , Microscopia Crioeletrônica , RNA Mitocondrial/metabolismo , RNA Mitocondrial/genética , RNA Mitocondrial/química , Metilação , Conformação de Ácido Nucleico , Modelos Moleculares , Precursores de RNA/metabolismo , Precursores de RNA/genética
19.
Cell Death Dis ; 15(6): 387, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824145

RESUMO

Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.


Assuntos
Tecido Adiposo , Diferenciação Celular , Epigênese Genética , Células-Tronco Mesenquimais , Mitocôndrias , Obesidade , Humanos , Células-Tronco Mesenquimais/metabolismo , Obesidade/metabolismo , Obesidade/genética , Obesidade/patologia , Mitocôndrias/metabolismo , Tecido Adiposo/metabolismo , Diferenciação Celular/genética , Feminino , Masculino , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Adulto , Pessoa de Meia-Idade , Proliferação de Células
20.
Sci Rep ; 14(1): 12602, 2024 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824202

RESUMO

Mitochondrial RNA modification (MRM) plays a crucial role in regulating the expression of key mitochondrial genes and promoting tumor metastasis. Despite its significance, comprehensive studies on MRM in lower grade gliomas (LGGs) remain unknown. Single-cell RNA-seq data (GSE89567) was used to evaluate the distribution functional status, and correlation of MRM-related genes in different cell types of LGG microenvironment. We developed an MRM scoring system by selecting potential MRM-related genes using LASSO regression analysis and the Random Survival Forest algorithm, based on multiple bulk RNA-seq datasets from TCGA, CGGA, GSE16011, and E-MTAB-3892. Analysis was performed on prognostic and immunological features, signaling pathways, metabolism, somatic mutations and copy number variations (CNVs), treatment responses, and forecasting of potential small-molecule agents. A total of 35 MRM-related genes were selected from the literature. Differential expression analysis of 1120 normal brain tissues and 529 LGGs revealed that 22 and 10 genes were upregulated and downregulated, respectively. Most genes were associated with prognosis of LGG. METLL8, METLL2A, TRMT112, and METTL2B were extensively expressed in all cell types and different cell cycle of each cell type. Almost all cell types had clusters related to mitochondrial RNA processing, ribosome biogenesis, or oxidative phosphorylation. Cell-cell communication and Pearson correlation analyses indicated that MRM may promoting the development of microenvironment beneficial to malignant progression via modulating NCMA signaling pathway and ICP expression. A total of 11 and 9 MRM-related genes were observed by LASSO and the RSF algorithm, respectively, and finally 6 MRM-related genes were used to establish MRM scoring system (TRMT2B, TRMT11, METTL6, METTL8, TRMT6, and TRUB2). The six MRM-related genes were then validated by qPCR in glioma and normal tissues. MRM score can predict the malignant clinical characteristics, abundance of immune infiltration, gene variation, clinical outcome, the enrichment of signaling pathways and metabolism. In vitro experiments demonstrated that silencing METTL8 significantly curbs glioma cell proliferation and enhances apoptosis. Patients with a high MRM score showed a better response to immunotherapies and small-molecule agents such as arachidonyl trifluoromethyl ketone, MS.275, AH.6809, tacrolimus, and TTNPB. These novel insights into the biological impacts of MRM within the glioma microenvironment underscore its potential as a target for developing precise therapies, including immunotherapeutic approaches.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Glioma/patologia , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral/genética , Processamento Pós-Transcricional do RNA , Gradação de Tumores , Mitocôndrias/genética , Mitocôndrias/metabolismo , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Multiômica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...