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1.
Artigo em Russo | MEDLINE | ID: mdl-34481432

RESUMO

OBJECTIVE: To study the effectiveness of a course of intravenous administration of cytoflavin in combination with a standard rehabilitation program for post-COVID fatigue syndrome caused by mitochondrial dysfunction. MATERIAL AND METHODS: The dynamic examination of 45 patients with post-COVID syndrome at the second stage of rehabilitation was carried out. The patients were subdivided into 2 groups comparable in gender and age. The volume of lung damage in patients of both groups was also comparable at range of 25-80%. Twenty-four patients of the control group were treated with the standard post-COVID rehabilitation protocol: pulse magnetic therapy, inhalation therapy, aeroion therapy, infrared laser therapy, course aerobic training, psychotherapy, and standard drug therapy. Twenty-one patients of the main group additionally received intravenous administration of cytoflavin daily for 10 days. The dynamics of the scores on the Rehabilitation Routing Scale, HDRS, the Asthenic Status Scale, and the 6-minute walk test was analyzed. RESULTS AND CONCLUSION: The additional intravenous administration of cytoflavin at the complex rehabilitation of post-COVID syndrome can significantly improve the therapeutic results: it significantly improves the overall functional state, reduces depression and fatigue level and increases tolerance to physical exertion.


Assuntos
COVID-19 , Fadiga/reabilitação , Mitocôndrias/patologia , COVID-19/reabilitação , Fadiga/virologia , Humanos , Resultado do Tratamento
2.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445555

RESUMO

Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.


Assuntos
Encéfalo/patologia , Estresse do Retículo Endoplasmático , Glândulas Mamárias Humanas/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Fatores de Transcrição/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Glândulas Mamárias Humanas/metabolismo , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360785

RESUMO

Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by WesTM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doxiciclina/farmacologia , Feminino , Células HT29 , Humanos , Células MCF-7 , Mitocôndrias/patologia , Sirolimo/farmacologia
4.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445210

RESUMO

Ischemic episodes are a leading cause of death worldwide with limited therapeutic interventions. The current study explored mitochondrial phosphate-activated glutaminase (GLS1) activity modulation by PKCßII through GC-MS untargeted metabolomics approach. Mitochondria were used to elucidate the endogenous resistance of hippocampal CA2-4 and dentate gyrus (DG) to transient ischemia and reperfusion in a model of ischemic episode in gerbils. In the present investigation, male gerbils were subjected to bilateral carotids occlusion for 5 min followed by reperfusion (IR). Gerbils were randomly divided into three groups as vehicle-treated sham control, vehicle-treated IR and PKCßII specific inhibitor peptide ßIIV5-3-treated IR. Vehicle or ßIIV5-3 (3 mg/kg, i.v.) were administered at the moment of reperfusion. The gerbils hippocampal tissue were isolated at various time of reperfusion and cell lysates or mitochondria were isolated from CA1 and CA2-4,DG hippocampal regions. Recombinant proteins PKCßII and GLS1 were used in in vitro phosphorylation reaction and organotypic hippocampal cultures (OHC) transiently exposed to NMDA (25 µM) to evaluate the inhibition of GLS1 on neuronal viability. PKCßII co-precipitates with GAC (GLS1 isoform) in CA2-4,DG mitochondria and phosphorylates GLS1 in vitro. Cell death was dose dependently increased when GLS1 was inhibited by BPTA while inhibition of mitochondrial pyruvate carrier (MPC) attenuated cell death in NMDA-challenged OHC. Fumarate and malate were increased after IR 1h in CA2-4,DG and this was reversed by ßIIV5-3 what correlated with GLS1 activity increases and earlier showed elevation of neuronal death (Krupska et al., 2017). The present study illustrates that CA2-4,DG resistance to ischemic episode at least partially rely on glutamine and glutamate utilization in mitochondria as a source of carbon to tricarboxylic acid cycle. This phenomenon depends on modulation of GLS1 activity by PKCßII and remodeling of MPC: all these do not occur in ischemia-vulnerable CA1.


Assuntos
Transtornos Cerebrovasculares/enzimologia , Glutaminase/metabolismo , Hipocampo/enzimologia , Mitocôndrias/enzimologia , Proteína Quinase C beta/metabolismo , Traumatismo por Reperfusão/enzimologia , Animais , Transtornos Cerebrovasculares/patologia , Gerbillinae , Hipocampo/patologia , Mitocôndrias/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia
5.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445229

RESUMO

Symbiosis between the mitochondrion and the ancestor of the eukaryotic cell allowed cellular complexity and supported life. Mitochondria have specialized in many key functions ensuring cell homeostasis and survival. Thus, proper communication between mitochondria and cell nucleus is paramount for cellular health. However, due to their archaebacterial origin, mitochondria possess a high immunogenic potential. Indeed, mitochondria have been identified as an intracellular source of molecules that can elicit cellular responses to pathogens. Compromised mitochondrial integrity leads to release of mitochondrial content into the cytosol, which triggers an unwanted cellular immune response. Mitochondrial nucleic acids (mtDNA and mtRNA) can interact with the same cytoplasmic sensors that are specialized in recognizing genetic material from pathogens. High-energy demanding cells, such as neurons, are highly affected by deficits in mitochondrial function. Notably, mitochondrial dysfunction, neurodegeneration, and chronic inflammation are concurrent events in many severe debilitating disorders. Interestingly in this context of pathology, increasing number of studies have detected immune-activating mtDNA and mtRNA that induce an aberrant production of pro-inflammatory cytokines and interferon effectors. Thus, this review provides new insights on mitochondria-driven inflammation as a potential therapeutic target for neurodegenerative and primary mitochondrial diseases.


Assuntos
Mitocôndrias/imunologia , Doenças Neurodegenerativas/imunologia , Animais , Citocinas/imunologia , DNA Mitocondrial/imunologia , Humanos , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , RNA Mitocondrial/imunologia
6.
Signal Transduct Target Ther ; 6(1): 308, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408131

RESUMO

Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.


Assuntos
COVID-19/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais , Proteínas Viroporinas/metabolismo , Células A549 , Animais , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Mitocôndrias/patologia , RNA-Seq , Células THP-1 , Células Vero
8.
Anim Sci J ; 92(1): e13608, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34405491

RESUMO

This study aims to investigate the morphology and distribution of mitochondria, spindles, and chromosomes in oocytes of aged mice and examine the effects of SRT1720 on oocyte maturation. C57BL/6J mice were divided into young (4-8 weeks) and aged groups (48-52 weeks). In vitro maturation media contained (0.05, 0.1, and 1.0 µM) SRT1720 and 0.1-µM dimethyl sulfoxide (DMSO control). The rate of chromosome misalignment and spindle misorientation in oocytes of aged mice were significantly higher than that of young mice (P < 0.01). Fluorescence intensity of mitochondria from oocytes of aged mice was significantly lower than that of young mice (P < 0.01). SRT1720 at 0.1 µM significantly improved oocyte maturation, fertilization, and blastocyst formation in aged mice compared with young mice (P < 0.01). Additionally, immunofluorescence intensity of mitochondria, normal spindle morphology, and chromosome alignment were notably enhanced with SRT1720 when compared with the DSMO control group for metaphase II (MII)-stage oocytes matured in vitro (P < 0.01); 0.1-µM SRT1720 enhanced the expression level of SRIT1 in oocytes from aged mice. In summary, the aged mice oocytes showed increased nuclear and cytoplasmic defects, whereas SRT1720 enhanced oocyte maturation and quality. We concluded that 0.1-µM SRT1720 was an appropriate concentration for in vitro maturation media.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Técnicas de Maturação in Vitro de Oócitos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Animais , Blastocisto , Cromossomos/metabolismo , Relação Dose-Resposta a Droga , Feminino , Fertilização/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oócitos/citologia , Oócitos/ultraestrutura , Fuso Acromático/metabolismo , Fuso Acromático/patologia
9.
Oxid Med Cell Longev ; 2021: 2989974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457111

RESUMO

In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.


Assuntos
Apoptose , Cardiomiopatias/patologia , Fibronectinas/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Sepse/patologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Fibronectinas/genética , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mitofagia , Miócitos Cardíacos/metabolismo , Ratos , Sepse/etiologia , Sepse/metabolismo
10.
Oxid Med Cell Longev ; 2021: 9990794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457121

RESUMO

Aims: This study is aimed at examining whether fatty acid synthase (FAS) can regulate mitochondrial function in hypoxia-induced pulmonary arterial hypertension (PAH) and its related mechanism. Results: The expression of FAS significantly increased in the lung tissue of mice with hypoxia-induced PAH, and its pharmacological inhibition by C75 ameliorated right ventricle cardiac function as revealed by echocardiographic analysis. Based on transmission electron microscopy and Seahorse assays, the mitochondrial function of mice with hypoxia was abnormal but was partially reversed after C75 injection. In vitro studies also showed an increase in the expression of FAS in hypoxia-induced human pulmonary artery smooth muscle cells (HPASMCs), which could be attenuated by FAS shRNA as well as C75 treatment. Meanwhile, C75 treatment reversed hypoxia-induced oxidative stress and activated PI3K/AKT signaling. shRNA-mediated inhibition of FAS reduced its expression and oxidative stress levels and improved mitochondrial respiratory capacity and ATP levels of hypoxia-induced HPASMCs. Conclusions: Inhibition of FAS plays a crucial role in shielding mice from hypoxia-induced PAH, which was partially achieved through the activation of PI3K/AKT signaling, indicating that the inhibition of FAS may provide a potential future direction for reversing PAH in humans.


Assuntos
4-Butirolactona/análogos & derivados , Metabolismo Energético , Ácido Graxo Sintases/antagonistas & inibidores , Hipóxia/complicações , Mitocôndrias/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , 4-Butirolactona/farmacologia , Animais , Apoptose , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/patologia , Transdução de Sinais
11.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360534

RESUMO

Inorganic phosphate (Pi) is an essential nutrient for living organisms and is maintained in equilibrium in the range of 0.8-1.4 mM Pi. Pi is a source of organic constituents for DNA, RNA, and phospholipids and is essential for ATP formation mainly through energy metabolism or cellular signalling modulators. In mitochondria isolated from the brain, liver, and heart, Pi has been shown to induce mitochondrial reactive oxygen species (ROS) release. Therefore, the purpose of this review article was to gather relevant experimental records of the production of Pi-induced reactive species, mainly ROS, to examine their essential roles in physiological processes, such as the development of bone and cartilage and the development of diseases, such as cardiovascular disease, diabetes, muscle atrophy, and male reproductive system impairment. Interestingly, in the presence of different antioxidants or inhibitors of cytoplasmic and mitochondrial Pi transporters, Pi-induced ROS production can be reversed and may be a possible pharmacological target.


Assuntos
Doenças Cardiovasculares/patologia , Diabetes Mellitus/patologia , Mitocôndrias/patologia , Atrofia Muscular/patologia , Fosfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/efeitos dos fármacos , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo
12.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360557

RESUMO

Among the eight human glutathione peroxidase isoforms, glutathione peroxidase 4 (GPX4) is the only enzyme capable of reducing complex lipid peroxides to the corresponding alcohols. In mice, corruption of the Gpx4 gene leads to embryonic lethality and more detailed expression silencing studies have implicated the enzyme in several physiological processes (e.g., embryonal cerebrogenesis, neuronal function, male fertility). Experiments with conditional knockout mice, in which expression of the Gpx4 gene was silenced in erythroid precursors, indicated a role of Gpx4 in erythropoiesis. To test this hypothesis in a cellular in vitro model we transfected mouse erythroleukemia cells with a Gpx4 siRNA construct and followed the expression kinetics of erythropoietic gene products. Our data indicate that Gpx4 is expressed at high levels in mouse erythroleukemia cells and that expression silencing of the Gpx4 gene delays in vitro erythropoiesis. However, heterozygous expression of a catalytically inactive Gpx4 mutant (Gpx4+/Sec46Ala) did not induce a defective erythropoietic phenotype in different in vivo and ex vivo models. These data suggest that Gpx4 plays a role in erythroid differentiation of mouse erythroleukemia cells but that heterozygous expression of a catalytically inactive Gpx4 is not sufficient to compromise in vivo and ex vivo erythropoiesis.


Assuntos
Eritropoese , Leucemia Eritroblástica Aguda/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , RNA Interferente Pequeno/genética , Animais , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
13.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360671

RESUMO

Regulated cell death (RCD) is a fundamental process common to nearly all living beings and essential for the development and tissue homeostasis in animals and humans. A wide range of molecules can induce RCD, including a number of viral proteolytic enzymes. To date, numerous data indicate that picornaviral 3C proteases can induce RCD. In most reported cases, these proteases induce classical caspase-dependent apoptosis. In contrast, the human hepatitis A virus 3C protease (3Cpro) has recently been shown to cause caspase-independent cell death accompanied by previously undescribed features. Here, we expressed 3Cpro in HEK293, HeLa, and A549 human cell lines to characterize 3Cpro-induced cell death morphologically and biochemically using flow cytometry and fluorescence microscopy. We found that dead cells demonstrated necrosis-like morphological changes including permeabilization of the plasma membrane, loss of mitochondrial potential, as well as mitochondria and nuclei swelling. Additionally, we showed that 3Cpro-induced cell death was efficiently blocked by ferroptosis inhibitors and was accompanied by intense lipid peroxidation. Taken together, these results indicate that 3Cpro induces ferroptosis upon its individual expression in human cells. This is the first demonstration that a proteolytic enzyme can induce ferroptosis, the recently discovered and actively studied type of RCD.


Assuntos
Proteases Virais 3C/metabolismo , Núcleo Celular/patologia , Ferroptose , Mitocôndrias/patologia , Proteases Virais 3C/genética , Células A549 , Núcleo Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Técnicas In Vitro , Peroxidação de Lipídeos , Mitocôndrias/metabolismo
14.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361072

RESUMO

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.


Assuntos
Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mitofagia , Neoplasias/patologia , Proteostase , Animais , Humanos , Neoplasias/etiologia , Neoplasias/metabolismo
15.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361091

RESUMO

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.


Assuntos
Encefalopatias/patologia , Metabolismo Energético , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Fosforilação Oxidativa , Animais , Encefalopatias/metabolismo , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo
16.
Molecules ; 26(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34279427

RESUMO

The functioning of mitochondria and their biogenesis are largely based on the proper function of the mitochondrial outer membrane channels, which selectively recognise and import proteins but also transport a wide range of other molecules, including metabolites, inorganic ions and nucleic acids. To date, nine channels have been identified in the mitochondrial outer membrane of which at least half represent the mitochondrial protein import apparatus. When compared to the mitochondrial inner membrane, the presented channels are mostly constitutively open and consequently may participate in transport of different molecules and contribute to relevant changes in the outer membrane permeability based on the channel conductance. In this review, we focus on the channel structure, properties and transported molecules as well as aspects important to their modulation. This information could be used for future studies of the cellular processes mediated by these channels, mitochondrial functioning and therapies for mitochondria-linked diseases.


Assuntos
Canais Iônicos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Membranas Mitocondriais/metabolismo , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Transporte Proteico
17.
Nat Commun ; 12(1): 4220, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244497

RESUMO

Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Córtex Cerebral/patologia , Ferroptose , Hormônios Gastrointestinais/metabolismo , Neuropeptídeos/metabolismo , Adulto , Idoso , Animais , Lesões Encefálicas Traumáticas/cirurgia , Células Cultivadas , Córtex Cerebral/citologia , Coenzima A Ligases/metabolismo , Modelos Animais de Doenças , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Hormônios Gastrointestinais/genética , Técnicas de Silenciamento de Genes , Humanos , Peroxidação de Lipídeos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/patologia , Neurônios/citologia , Neurônios/patologia , Neuropeptídeos/genética , Fosfolipídeos/biossíntese , Cultura Primária de Células , Proteólise , Ubiquitinação
18.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299170

RESUMO

Previous research has shown that a perinatal obesogenic, high-fat diet (HFD) is able to exacerbate ozone-induced adverse effects on lung function, injury, and inflammation in offspring, and it has been suggested that mitochondrial dysfunction is implicated herein. The aim of this study was to investigate whether a perinatal obesogenic HFD affects ozone-induced changes in offspring pulmonary oxidant status and the molecular control of mitochondrial function. For this purpose, female Long-Evans rats were fed a control diet or HFD before and during gestation, and during lactation, after which the offspring were acutely exposed to filtered air or ozone at a young-adult age (forty days). Directly following this exposure, the offspring lungs were examined for markers related to oxidative stress; oxidative phosphorylation; and mitochondrial fusion, fission, biogenesis, and mitophagy. Acute ozone exposure significantly increased pulmonary oxidant status and upregulated the molecular machinery that controls receptor-mediated mitophagy. In female offspring, a perinatal HFD exacerbated these responses, whereas in male offspring, responses were similar for both diet groups. The expression of the genes and proteins involved in oxidative phosphorylation and mitochondrial biogenesis, fusion, and fission was not affected by ozone exposure or perinatal HFD. These findings suggest that a perinatal HFD influences ozone-induced responses on pulmonary oxidant status and the molecular control of mitophagy in female rat offspring.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Pulmão/patologia , Mitocôndrias/patologia , Mitofagia , Oxidantes/metabolismo , Ozônio/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Feminino , Perfilação da Expressão Gênica , Pulmão/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Long-Evans
19.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207557

RESUMO

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5'-cyclopurine-2'-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.


Assuntos
Reparo do DNA , Doenças Neurodegenerativas , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismo , Xeroderma Pigmentoso/patologia
20.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207660

RESUMO

Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Endopeptidase Clp/metabolismo , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Endopeptidase Clp/genética , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia
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