Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 132.009
Filtrar
1.
Biomed Pharmacother ; 153: 113451, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076564

RESUMO

Mitochondria play a crucial part in the cell's ability to adapt to the changing microenvironments and their dysfunction is associated with an extensive array of illnesses, including cancer. Mitochondrial dysfunction has been identified as a potential therapeutic target for cancer therapy. The objective of this article is to give an in-depth analysis of cancer treatment that targets the mitochondrial genome at the molecular level. Recent studies provide insights into nanomedicine techniques and theranostic nanomedicine for mitochondrial targeting. It also provides conceptual information on mitochondrial biomarkers for cancer treatment. Major drawbacks and challenges involved in mitochondrial targeting for advanced cancer therapy have also been discussed. There is a lot of evidence and reason to support using nanomedicine to focus on mitochondrial function. The development of a delivery system with increased selectivity and effectiveness is a prerequisite for a theranostic approach to cancer treatment. If given in large amounts, several new cancer-fighting medicines have been created that are toxic to healthy cells as well. For effective therapy, a new drug must be developed rather than an old one. When it comes to mitochondrial targeting therapy, theranostic techniques offer valuable insight.


Assuntos
Neoplasias , Nanomedicina Teranóstica , Biomarcadores , Humanos , Mitocôndrias , Nanomedicina/métodos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Microambiente Tumoral
2.
Biomed Pharmacother ; 153: 113482, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076582

RESUMO

Mesenchymal stem cells (MSCs) have therapeutic value in many diseases. Mitochondria transfer can promote wound healing and can potentially be applied to the repair of damaged tissue, but the specific mechanisms and regulatory factors involved remain unclear. In this review, we discuss the mechanistic basis of mitochondria transfer and factors that restore mitochondrial function in injured somatic cells.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias
3.
Biomed Pharmacother ; 153: 113484, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076583

RESUMO

Increasing mitochondrial fusion by intra-tumoral grafting of membrane-fused mitochondria created with Pep-1 conjugation (P-Mito) contributes to breast cancer treatment, but it needs to be validated. Using mitochondrial division inhibitor-1 (Mdivi-1, Mdi) to disturb mitochondrial dynamics, we showed that the antitumor action of P-Mito in a mouse model of triple-negative breast cancer depends upon mitochondrial fusion and that Mdi treatment alone is ineffective. P-Mito significantly enhanced Doxorubicin (Dox) sensitivity by inducing mitochondrial fusion and mitophagy, and the same efficiency was also achieved with Mdi by inhibiting mitophagy. Cell death was induced via the p53 pathway and AIF nuclear translocation in the case of P-Mito, versus the caspase-dependent pathway for Mdi. Notably, both mitochondrial treatments reduced oxidative stress and blood vessel density of xenograft tumors, especially P-Mito, which was accompanied by inhibition of nuclear factor kappa-B activation. Furthermore, through enrichment analysis, four microRNAs in serum microvesicles induced by P-Mito caused expression of predicted targets via the PI3K-Akt pathway, and significantly impacted regulation of nuclear processes and myeloid cell differentiation. Clustering of gene-sets implicated a major steroid catabolic network. This study showed diverse roles of mitochondria in breast cancer and revealed effective adjuvant therapy targeting mitochondrial fusion and mitophagy.


Assuntos
Mitofagia , Neoplasias de Mama Triplo Negativas , Animais , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Humanos , Camundongos , Mitocôndrias , Dinâmica Mitocondrial , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
4.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4305-4313, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046856

RESUMO

Cerebral ischemia-reperfusion injury(CIRI) is an important factor hindering the recovery of ischemic stroke patients after blood flow recanalization. Mitochondria, serving as the "energy chamber" of cells, have multiple important physiological functions, such as supplying energy, metabolizing reactive oxygen species, storing calcium, and mediating programmed cell death. During CIRI, oxidative stress, calcium overload, inflammatory response, and other factors can easily lead to neuronal mitochondrial dyshomeostasis, which is the key pathological link leading to secondary injury. As reported, the mitochondrial quality control(MQC) system, mainly including mitochondrial biosynthesis, kinetics, autophagy, and derived vesicles, is an important endogenous mechanism to maintain mitochondrial homeostasis and plays an important protective role in the damage of mitochondrial structure and function caused by CIRI. This paper reviewed the mechanism of MQC and the research progress on MQC-targeting therapy of CIRI in recent 10 years to provide theoretical references for exploring new strategies for the prevention and treatment of ischemic stroke with traditional Chinese medicine.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Traumatismo por Reperfusão , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevenção & controle , Cálcio/metabolismo , Humanos , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle
5.
J Neuroinflammation ; 19(1): 213, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050772

RESUMO

BACKGROUND: Chronic kidney disease (CKD), characterized as renal dysfunction, is regarded as a major public health problem which carries a high risk of cardiovascular diseases. The purpose of this study is to evaluate the functional significance of Drp1 in hypercalcemia-associated neuronal damage following CKD and the associated mechanism. METHODS: Initially, the CKD mouse models were established. Next, RT-qPCR and Western blot analysis were performed to measure expression of Fis1 and Drp1 in CKD. Chromatin immunoprecipitation (ChIP) assay and dual-luciferase reporter gene assay were utilized to explore the relationship among Drp1, HIF-1α, EZH2, and ROS with primary cortical neurons isolated from neonatal mice. Next, CKD mice were subjected to calcitonin treatment or manipulation with adenovirus expressing sh-Drp1, so as to explore the effects of Drp1 on hypercalcemia-induced neuronal injury in CKD. TUNEL assay and immunofluorescence staining were performed to detect apoptosis and NeuN-positive cells (neurons) in prefrontal cortical tissues of CKD mice. RESULTS: It was found that hypercalcemia could induce neuronal injury in CKD mice. An increase of Fis1 and Drp1 expression in cerebral cortex of CKD mice correlated with mitochondrial fragmentation. Calcitonin suppressed Drp1/Fis1-mediated mitochondrial fragmentation to attenuate hypercalcemia-induced neuronal injury after CKD. Additionally, Drp1 could increase EZH2 expression through the binding of HIF-1α to EZH2 promoter via elevating ROS generation. Furthermore, Drp1 knockdown inhibited hypercalcemia-induced neuronal injury in CKD while overexpression of EZH2 could reverse this effect in vivo. CONCLUSION: Taken together, the key findings of the current study demonstrate the promotive role of Drp1 in mitochondrial fragmentation which contributes to hypercalcemia-induced neuronal injury in CKD.


Assuntos
Dinaminas/metabolismo , Hipercalcemia , Mitocôndrias , Insuficiência Renal Crônica , Animais , Apoptose , Calcitonina/metabolismo , Calcitonina/farmacologia , Modelos Animais de Doenças , Dinaminas/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Hipercalcemia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo
6.
Adipocyte ; 11(1): 562-571, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36053001

RESUMO

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA's effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.


Assuntos
Diabetes Mellitus Tipo 2 , Biogênese de Organelas , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/metabolismo , Animais , Ácidos Cafeicos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , DNA Mitocondrial/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Lactatos , Camundongos , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
7.
Nat Commun ; 13(1): 5202, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36057633

RESUMO

Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid ß-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Espermidina , Animais , Ácidos Graxos , Lisina/metabolismo , Camundongos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fatores de Iniciação de Peptídeos/genética , Fatores de Iniciação de Peptídeos/metabolismo , Espermidina/farmacologia
8.
Mol Med ; 28(1): 103, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058905

RESUMO

BACKGROUND: Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive. METHODS: We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration. RESULTS: We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity. CONCLUSIONS: Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.


Assuntos
Injúria Renal Aguda , Sepse , Injúria Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Inflamassomos/metabolismo , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Fatores de Iniciação de Peptídeos/farmacologia , Fatores de Iniciação de Peptídeos/uso terapêutico , Respiração , Sepse/metabolismo , Espermidina/metabolismo , Espermidina/farmacologia , Espermidina/uso terapêutico
9.
Cell Metab ; 34(9): 1231-1233, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36070679

RESUMO

In this issue of Cell Metabolism, Xue et al. propose that the mitochondrial calcium uniporter (MCU) binds uncoupling protein 1 (UCP1) via the MCU regulator (EMRE) to form a protein complex that the authors term the "thermoporter." Through gain- and loss-of-function experiments, the authors infer that the thermoporter promotes calcium influx into the mitochondrial matrix to enhance NADH production, which supports thermogenesis in brown adipose tissue (BAT).


Assuntos
Tecido Adiposo Marrom , Cálcio , Tecido Adiposo Marrom/metabolismo , Cálcio/metabolismo , Mitocôndrias/metabolismo , Termogênese , Proteína Desacopladora 1/metabolismo
10.
J Transl Med ; 20(1): 410, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071497

RESUMO

Mitochondria-induced cell death is a vital mechanism of heart failure (HF). Thus, identification of mitochondria-related genes (Mito-RGs) based on transcriptome sequencing data of HF might provide novel diagnostic markers and therapeutic targets for HF. First, bioinformatics analysis was conducted on the GSE57338, GSE76701, GSE136547, and GSE77399 datasets in the Gene Expression Omnibus. Next, we analyzed HF-Mito differentially expressed genes (DEGs) using the protein-protein interaction (PPI) network for obtaining critical genes and exploring their functions. Subsequently, immune cell scores of the HF and normal groups were compared. The potential alteration mechanisms of the key genes were investigated by constructing a competing endogenous RNA network. Finally, we predicted potential therapeutic agents and validated the expression levels of the key genes. Twenty-three HF-Mito DEGs were acquired in the GSE57338 dataset, and the PPI network obtained four key genes, including IFIT3, XAF1, RSAD2, and MX1. According to gene set enrichment analysis, the key genes showed high enrichment in myogenesis and hypoxia. Immune cell analysis demonstrated that aDCs, B cells, and 20 other immune cell types varied between the HF and normal groups. Moreover, we observed that H19 might affect the expression of IFIT3, AXF1, and RSAD2. PCGEM1 might regulate RSAD2 expression. A total of 515 potential therapeutic drugs targeting the key genes, such as tretinoin, silicon dioxide, and bisphenol A, were acquired. Finally, IFIT3, RSAD2, and MX1 expression increased in HF samples compared with normal samples in the GSE76701 dataset, conforming to the GSE57338 dataset analysis. This work screened four key genes, namely, IFIT3, XAF1, RSAD2, and MX1, which can be further explored in subsequent studies for their specific molecular mechanisms in HF.


Assuntos
Redes Reguladoras de Genes , Insuficiência Cardíaca , Perfilação da Expressão Gênica , Insuficiência Cardíaca/genética , Humanos , Mitocôndrias/genética , Mapas de Interação de Proteínas/genética
11.
Cell Commun Signal ; 20(1): 137, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071528

RESUMO

BACKGROUND: Synovitis (SI) is one of the most common and serious orthopedic diseases in horses of different age, breed and sex, which contributes to the development of osteoarthritis. The burden of SI includes economic loss and represents a real challenge for current veterinary health care. At the molecular level, fibroblasts-like synoviocytes (FLS) are recognized as major cell populations involved in SI pathogenesis. In the course of SI, FLSs are losing their protective and pro-regenerative cytological features, become highly proliferative and initiate various stress signaling pathways. METHODS: Fibroblast-like synoviocytes were treated with LPS in order to generate SI in vitro model. Mitochondria were isolated from peripheral blood derived mononuclear cells and co-cultured with FLS. After 24 h of culture, cells were subjected to RT-qPCR, western blot, cytometric and confocal microscopy analysis. RESULTS: Mitochondrial transfer (MT) was observed in vitro studies using confocal microscopy. Further studies revealed, that MT to LPS-treated FLS reduced cell proliferation, modulated apoptosis and decreased inflammatory response. Overall, MT Resulted in the considerable recovery of recipient cells cytophysiological properties. CONCLUSIONS: Presented data provides evidence that mitochondria transfersignificantly modulate FLS proliferative and metabolic activity through improved mitochondrial biogenesis and dynamics in activated FLS. Obtained results for the first time demonstrate that horizontal MT might be considered as a therapeutic tool for synovitis treatment; however, further clinical studies are strongly required. Video abstract.


Assuntos
Sinoviócitos , Sinovite , Animais , Células Cultivadas , Fibroblastos/metabolismo , Cavalos , Lipopolissacarídeos/farmacologia , Mitocôndrias , Sinoviócitos/metabolismo , Sinovite/metabolismo
12.
J Immunotoxicol ; 19(1): 81-92, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36067115

RESUMO

Cadmium (Cd) is an immunotoxic metal frequently found in the environment. The in vitro study undertaken here evaluated the immunotoxic effects of Cd in isolated human peripheral blood monocytes (hPBM). The results of the studies of exposures to varying doses of Cd (0, 0.1, 1, 10, and 100 µM, as cadmium dichloride [CdCl2]) for 3, 6, 12, 24, 48, and 72 hr showed the test agent was cytotoxic to the cells in time- and concentration-related manners. Thereafter, using only those doses found to not cause extreme cell lethality a 48-hr period, the impact of 0.1 or 1 µM CdCl2 on the cells was evaluated. Functionally, CdCl2 treatment led to time- and concentration-related decreases in hPBM phagocytic activities as well as in the ability of the cells to form/release cytokines (including tumor necrosis factor [TNF]-α and interleukin [IL]-6 and -8). The CdCl2 also led to significantly decreased ATP production (in part, via inhibition of mitochondrial complexes I and III) as well as in mitochondrial membrane potentials (MMP) and oxygen consumption rates (OCR; associated with parallel increases in cell lactate production) in the cells. In addition, CdCl2 treatment resulted in significant increases in mitochondrial membrane fluidity (MMF) and cell unsaturated fatty acid content. Based on the results here, one might conclude that some of the effects that arose during the CdCl2-induced dysfunction of the isolated hPBM (i.e. changes phagocytic activity, cytokine formation/secretion) could have evolved secondary to CdCl2-induced disruptions of hPBM cell bioenergetics - an effect that itself was a culmination of an overall toxicity from CdCl2 upon the mitochondria within these cells.


Assuntos
Cádmio , Monócitos , Cádmio/metabolismo , Cádmio/toxicidade , Cloreto de Cádmio/metabolismo , Cloreto de Cádmio/toxicidade , Humanos , Mitocôndrias , Fator de Necrose Tumoral alfa/metabolismo
13.
Anal Chim Acta ; 1226: 340192, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36068051

RESUMO

Viscosity is an essential microenvironmental parameter, which is related to various diseases such as acute inflammation. So it is necessary to develop a probe to monitor viscosity changes during the inflammatory progression in vivo. Herein, a HPQ (2-(2'-hydroxyphenyl)-4(3H)-quinazolinone)-based fluorescent probe named HPQ-BI-V is prepared for detecting viscosity in biological systems. The introduction of benzindole groups extends the π conjugation of HPQ, resulting in far-red emission wavelength at 610 nm. When the viscosity raises from 3.11 cP to 567.1 cP, the fluorescence signal increases 711 times, indicating the high sensitivity of the probe. Furthermore, this probe displays excellent selectivity for viscosity in comparison with other interfering analytes. Furthermore, the probe has excellent photostability and outstanding response capability in the physiological pH range. Given these advantages, HPQ-BI-V can be applied for detecting viscosity changes in HepG2 cells and zebrafish. In particular, the probe can successfully visualize viscosity changes in acute inflammatory mice induced by LPS and the assessment of anti-inflammatory drug.


Assuntos
Corantes Fluorescentes , Peixe-Zebra , Animais , Modelos Animais de Doenças , Células HeLa , Humanos , Inflamação/induzido quimicamente , Camundongos , Mitocôndrias , Viscosidade
14.
Oxid Med Cell Longev ; 2022: 7086807, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052160

RESUMO

Mitochondria-associated membranes (MAMs), physical connection sites between the endoplasmic reticulum (ER) and the outer mitochondrial membrane (OMM), are involved in numerous cellular processes, such as calcium ion transport, lipid metabolism, autophagy, ER stress, mitochondria morphology, and apoptosis. Autophagy is a highly conserved intracellular process in which cellular contents are delivered by double-membrane vesicles, called autophagosomes, to the lysosomes for destruction and recycling. Autophagy, typically triggered by stress, eliminates damaged or redundant protein molecules and organelles to maintain regular cellular activity. Dysfunction of MAMs or autophagy is intimately associated with various diseases, including aging, cardiovascular, infections, cancer, multiple toxic agents, and some genetic disorders. Increasing evidence has shown that MAMs play a significant role in autophagy development and maturation. In our study, we concentrated on two opposing functions of MAMs in autophagy: facilitating the formation of autophagosomes and inhibiting autophagy. We recognized the link between MAMs and autophagy in the occurrence and progression of the diseases and therefore collated and summarized the existing intrinsic molecular mechanisms. Furthermore, we draw attention to several crucial data and open issues in the area that may be helpful for further study.


Assuntos
Retículo Endoplasmático , Membranas Mitocondriais , Autofagia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo
15.
Arch Microbiol ; 204(9): 593, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36053319

RESUMO

The purpose of this study was to determine the cytotoxicity of Lactiplantibacillus plantarum strain RD1 (Lpb RD1), which was isolated and identified from the curd by 16 S rRNA sequencing. The probiotic properties of the isolated strain were studied by bile and NaCl tolerance and the ethyl acetate extract of Ea-LpRD1, was used to determine the toxicity against human breast cancer (MCF-7) cell lines and human embryonic kidney (HEK-293) cell lines by MTT assay. DNA fragmentation assay was carried out to study apoptosis induction. Flow cytometry analysis was done to determine the % of a cell population using the FTIC-Annexin V staining method. RT-PCR was used to assess gene expression levels in both cell lines. The IC50 concentration of the Ea-LpRD1 in MCF-7 cells was 0.30 mg/ml and in HEK-293 was 0.47 mg/ml. The expression levels of the BCL-2 gene anti-apoptotic genes in humans were reduced and BAX, caspase-8, caspase-3, and caspase-9 were an increased expression in MCF-7 cell lines.


Assuntos
Apoptose , Mitocôndrias , Fragmentação do DNA , Células HEK293 , Humanos , Células MCF-7 , Mitocôndrias/genética , Mitocôndrias/metabolismo
16.
Mol Cell ; 82(17): 3119-3121, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055204

RESUMO

In this issue of Molecular Cell, Wang et al. investigate the Warburg effect in proliferating cells and demonstrate that lactate fermentation is a secondary mechanism activated after mitochondrial shuttles exceed their capacity to oxidize cytosolic NADH.


Assuntos
Mitocôndrias , NAD , Fermentação , Glicólise , Lactatos/metabolismo , Mitocôndrias/metabolismo , NAD/metabolismo , Oxirredução
17.
Nat Commun ; 13(1): 5164, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056001

RESUMO

Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the mitochondrial outer membrane. Strikingly, a number of conditions, including mitochondrial protein misfolding, can induce mitophagy without a loss in membrane potential. The underlying molecular details remain unclear. Here, we report that a loss of mitochondrial protein import, mediated by the pre-sequence translocase-associated motor complex PAM, is sufficient to induce mitophagy in polarized mitochondria. A genome-wide CRISPR/Cas9 screen for mitophagy inducers identifies components of the PAM complex. Protein import defects are able to induce mitophagy without a need for depolarization. Upon mitochondrial protein misfolding, PAM dissociates from the import machinery resulting in decreased protein import and mitophagy induction. Our findings extend the current mitophagy model to explain mitophagy induction upon conditions that do not affect membrane polarization, such as mitochondrial protein misfolding.


Assuntos
Mitofagia , Proteínas Quinases , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
18.
Commun Biol ; 5(1): 900, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056095

RESUMO

Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.


Assuntos
Canais de Cálcio , Proteínas de Transporte da Membrana Mitocondrial , Potenciais de Ação , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , NAD/metabolismo , Células Piramidais/metabolismo
19.
Acta Biochim Pol ; 69(3): 513-522, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36049068

RESUMO

In recent years, the accumulation of phosphate ions and the increase in acidity have been described as crucial metabolic fatigue-leading factors that disturb muscle fiber contractions. This fact is especially important in the context of mitochondrial dysfunctions in which excessive fatigue is one of the possible symptoms. However, little is known about the precise fatigue-inducing thresholds of work intensity in mitochondrial dysfunctions of various types and at various stages of their severity. Possible interactions of additional factors such as disturbances in electrolyte concentrations (i.e. magnesium ions) were also not precisely defined. One of the best-suited tools for this kind of problem is systems biology, which enables modeling of metabolic pathways. In this research, a computer model of working skeletal muscle was adapted. The relationship between the decrease in oxidative phosphorylation and the workload shows a linear dependence for dysfunctions that evenly disturb the activity of each element of the pathway (which is equivalent to the decrease in mitochondrial mass). In case of dysfunctions that disrupt only one element of the pathway, the relationship between fatigue threshold and exercise intensity is exponential, but with higher threshold deficiency values. Muscle phosphate levels were the most vulnerable to disruptions of complex III and ATP synthase. Surprisingly, disruptions of the ATP/ADP exchanger emerged as equally disruptive and capable of significantly increasing phosphate concentrations also in the rest state, whereas the impact of the impairment of the phosphate transporter was negligible. Perturbations in magnesium concentration also did not show a significant effect in any of these models.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons , Magnésio , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Simulação por Computador , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/farmacologia , Fadiga/metabolismo , Humanos , Magnésio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte de Fosfato/metabolismo , Fosfatos
20.
J Dairy Sci ; 105(10): 8509-8522, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055854

RESUMO

Telomeres cap the ends of eukaryotic chromosomes, and the telomere length (TL) is related to cellular age. The mitochondrial DNA copy number (mtDNAcn) reflects the abundance of mitochondria in a cell. In addition to generating energy, mitochondria are also the main producers of reactive oxygen species, which in turn can accelerate TL attrition and impair mitochondrial function. Nutrition in early life could influence mtDNAcn and TL in later life. In the present study, we investigated the effects of feeding different levels of milk replacer (MR) on TL shortening and energetic status by examining mtDNAcn of heifers during their first year of life. In this study, whole blood samples were obtained from German Holstein heifer calves 36 to 48 h after birth (wk 1) and at wk 12 and wk 16 of life (n = 37), as well as from 31 calves when reaching 1 yr of age. Calves were fed either a high level of MR (14% solids) at 10 L/d (1.4 kg of MR/d; n = 18) or a restrictive low level at 5.7 L/d (0.8 kg of MR/d; n = 19) until linear weaning in wk 13 to 14 of life. Additional whole blood samples were taken from their respective dams 36 to 48 h after calving. Relative TL (qT) and mtDNAcn in cells from whole blood were measured by multiplex quantitative PCR. The greatest qT values were observed in neonates (36-48 h after birth), with decreasing qT values thereafter. Delta qT values were calculated as ΔqT = qT (first year of life) - initial qT (36-48 h after birth). We found no effect of the feeding regimen on qT values, but qT decreased with age. The mtDNAcn was lowest in neonates, increased until wk 12 of life, and then remained at a constant level until after weaning (wk 16). After the first year of life, mtDNAcn was decreased and returned to levels comparable to those of the neonatal stage. No differences in mtDNAcn were detectable between feeding groups within each time point. When comparing the values of qT and mtDNAcn between the calves and their dams after calving (36-48 h after birth and after calving), greater values were observed in calves than in dams. Delta qT values were negative in all but 2 calves (on the restricted diet), indicating that the change in TL with age was not uniform among individual animals, whereas no difference in mean ΔqT values occurred between the feeding groups. Additional analyses of the correlation between qT, mtDNAcn, and various indicators of oxidative status from birth until wk 16 of life did not indicate major interactions between oxidative status, qT and mtDNAcn. The results of this study support an age-dependent decrease of TL in calves independent of the MR feeding level and show the dynamic changes of mtDNAcn in early life.


Assuntos
Ração Animal , Dieta , Ração Animal/análise , Animais , Bovinos , Variações do Número de Cópias de DNA , DNA Mitocondrial , Dieta/veterinária , Feminino , Leite/metabolismo , Mitocôndrias , Espécies Reativas de Oxigênio/metabolismo , Telômero , Desmame
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...