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1.
Front Endocrinol (Lausanne) ; 15: 1417007, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38952389

RESUMO

Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotal mechanisms through which mitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health.


Assuntos
Envelhecimento , Mitocôndrias , Ovário , Humanos , Feminino , Mitocôndrias/metabolismo , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Ovário/metabolismo , Ovário/fisiologia , Animais , Antioxidantes/uso terapêutico , Oócitos/metabolismo , Oócitos/fisiologia , Mitofagia/fisiologia
2.
Cell Death Dis ; 15(7): 473, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956064

RESUMO

Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.


Assuntos
Injúria Renal Aguda , Fatores Inibidores da Migração de Macrófagos , Mitofagia , Proteínas Quinases , Sepse , Ubiquitina-Proteína Ligases , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases/metabolismo , Sepse/complicações , Sepse/metabolismo , Animais , Humanos , Mitocôndrias/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Apoptose , Ligação Proteica , Masculino , Oxirredutases Intramoleculares/metabolismo
3.
World J Gastroenterol ; 30(23): 2934-2946, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38946875

RESUMO

In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was published in a recent issue of the World Journal of Gastroenterology. We focused on the statement that "autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal cells". With advancing research, autophagy, and particularly the pivotal role of the macroautophagy in maintaining cellular equilibrium and stress response in the gastrointestinal system, has garnered extensive study. However, the significance of mitophagy, a unique selective autophagy pathway with ubiquitin-dependent and independent variants, should not be overlooked. In recent decades, mitophagy has been shown to be closely related to the occurrence and development of gastrointestinal diseases, especially inflammatory bowel disease, gastric cancer, and colorectal cancer. The interplay between mitophagy and mitochondrial quality control is crucial for elucidating disease mechanisms, as well as for the development of novel treatment strategies. Exploring the pathogenesis behind gastrointestinal diseases and providing individualized and efficient treatment for patients are subjects we have been exploring. This article reviews the potential mechanism of mitophagy in gastrointestinal diseases with the hope of providing new ideas for diagnosis and treatment.


Assuntos
Autofagia , Gastroenteropatias , Mitocôndrias , Mitofagia , Humanos , Autofagia/fisiologia , Gastroenteropatias/patologia , Gastroenteropatias/metabolismo , Gastroenteropatias/fisiopatologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/metabolismo , Animais
4.
PeerJ ; 12: e17664, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38974415

RESUMO

Objective: To study the mechanism by which conditioned medium of bone marrow mesenchymal stem cells (BMSCs-CM) facilitates the transition of pro-inflammatory polarized microglia to an anti-inflammatory phenotype. Methods: BV2 cells, a mouse microglia cell line, were transformed into a pro-inflammatory phenotype using lipopolysaccharide. The expression of phenotypic genes in BV2 cells was detected using real-time quantitative PCR (RT-qPCR). Enzyme-linked immunosorbent assay was used to measure inflammatory cytokine levels in BV2 cells co-cultured with BMSCs-CM. The expressions of mitophagy-associated proteins were determined using western blot. The mitochondrial membrane potential and ATP levels in BV2 cells were measured using JC-1 staining and an ATP assay kit, respectively. Additionally, we examined the proliferation, apoptosis, and migration of C8-D1A cells, a mouse astrocyte cell line, co-cultured with BV2 cells. Results: After co- culture with BMSCs -CM, the mRNA expression of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase significantly decreased in pro-inflammatory BV2 cells, whereas the expression of CD206 and arginase-1 significantly increased. Moreover, TNF-α and interleukin-6 levels significantly decreased, whereas transforming growth factor-ß and interleukin-10 levels significantly increased. Furthermore, co-culture with BMSCs-CM increased mitophagy-associated protein expression, ATP levels, mitochondrial and lysosomal co-localization in these cells and decreased reactive oxygen species levels. Importantly, BMSCs-CM reversed the decrease in the proliferation and migration of C8-D1A cells co-cultured with pro-inflammatory BV2 cells and inhibited the apoptosis of C8-D1A cells. Conclusion: BMSCs-CM may promote the transition of polarized microglia from a pro-inflammatory to an anti-inflammatory phenotype by regulating mitophagy and influences the functional state of astrocytes.


Assuntos
Autofagia , Técnicas de Cocultura , Células-Tronco Mesenquimais , Microglia , Mitocôndrias , Animais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Microglia/metabolismo , Camundongos , Meios de Cultivo Condicionados/farmacologia , Mitocôndrias/metabolismo , Fenótipo , Linhagem Celular , Mitofagia , Proliferação de Células , Citocinas/metabolismo , Apoptose , Lipopolissacarídeos/farmacologia
5.
Nat Commun ; 15(1): 5715, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977659

RESUMO

Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane. LC3-associated phagocytosis cascade of events, including recruitment of a Rubicon-based class III PI(3)K complex to the flagellum vesicular sheaths, its activation, and consequent recruitment of Atg8/LC3, are all required for paternal mitochondrial elimination. Finally, lysosomes fuse with strings of large vesicles derived from the flagellum vesicular sheaths and contain degrading fragments of the paternal mitochondrial derivative. Given reports showing that in some mammals, the paternal mitochondria are also decorated with Atg8/LC3 and surrounded by multivesicular bodies upon fertilization, our findings suggest that a similar pathway also mediates paternal mitochondrial elimination in other flagellated sperm-producing organisms.


Assuntos
Proteínas de Drosophila , Fertilização , Mitocôndrias , Corpos Multivesiculares , Fagocitose , Espermatozoides , Animais , Mitocôndrias/metabolismo , Masculino , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Feminino , Espermatozoides/metabolismo , Corpos Multivesiculares/metabolismo , Drosophila melanogaster/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Óvulo/metabolismo , Lisossomos/metabolismo , Cauda do Espermatozoide/metabolismo , Mitofagia
6.
Cell Death Dis ; 15(7): 484, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969639

RESUMO

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.


Assuntos
Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético , Neoplasias Hepáticas , Proteínas de Membrana , Mitofagia , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/farmacologia , Mitofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Proteínas de Membrana/metabolismo , Metabolismo Energético/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas/metabolismo , Camundongos , Camundongos Nus , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos BALB C , Reprogramação Metabólica
7.
Theranostics ; 14(9): 3719-3738, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948070

RESUMO

Rationale: Autophagy dysregulation is known to be a mechanism of doxorubicin (DOX)-induced cardiotoxicity (DIC). Mitochondrial-Endoplasmic Reticulum Contacts (MERCs) are where autophagy initiates and autophagosomes form. However, the role of MERCs in autophagy dysregulation in DIC remains elusive. FUNDC1 is a tethering protein of MERCs. We aim to investigate the effect of DOX on MERCs in cardiomyocytes and explore whether it is involved in the dysregulated autophagy in DIC. Methods: We employed confocal microscopy and transmission electron microscopy to assess MERCs structure. Autophagic flux was analyzed using the mCherry-EGFP-LC3B fluorescence assay and western blotting for LC3BII. Mitophagy was studied through the mCherry-EGFP-FIS1 fluorescence assay and colocalization analysis between LC3B and mitochondria. A total dose of 18 mg/kg of doxorubicin was administrated in mice to construct a DIC model in vivo. Additionally, we used adeno-associated virus (AAV) to cardiac-specifically overexpress FUNDC1. Cardiac function and remodeling were evaluated by echocardiography and Masson's trichrome staining, respectively. Results: DOX blocked autophagic flux by inhibiting autophagosome biogenesis, which could be attributed to the downregulation of FUNDC1 and disruption of MERCs structures. FUNDC1 overexpression restored the blocked autophagosome biogenesis by maintaining MERCs structure and facilitating ATG5-ATG12/ATG16L1 complex formation without altering mitophagy. Furthermore, FUNDC1 alleviated DOX-induced oxidative stress and cardiomyocytes deaths in an autophagy-dependent manner. Notably, cardiac-specific overexpression of FUNDC1 protected DOX-treated mice against adverse cardiac remodeling and improved cardiac function. Conclusions: In summary, our study identified that FUNDC1-meditated MERCs exerted a cardioprotective effect against DIC by restoring the blocked autophagosome biogenesis. Importantly, this research reveals a novel role of FUNDC1 in enhancing macroautophagy via restoring MERCs structure and autophagosome biogenesis in the DIC model, beyond its previously known regulatory role as an mitophagy receptor.


Assuntos
Autofagia , Cardiotoxicidade , Doxorrubicina , Retículo Endoplasmático , Proteínas de Membrana , Proteínas Mitocondriais , Miócitos Cardíacos , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Camundongos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Masculino , Autofagossomos/metabolismo , Autofagossomos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
8.
Cell Biochem Funct ; 42(5): e4085, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38951992

RESUMO

This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents evidence that the dysregulation of calcium (Ca2+) homeostasis, along with mitochondrial dysfunction and aberrant autophagic processes, may drive the disease's progression during its asymptomatic, preclinical stage. Understanding the intricate molecular interplay that unfolds during this critical period offers a window into identifying novel therapeutic targets, thereby advancing the treatment of neurodegenerative disorders. The review delves into both established and emerging insights into the molecular alterations precipitated by the disruption of Ca2+ balance, setting the stage for cognitive decline and neurodegeneration.


Assuntos
Doença de Alzheimer , Autofagia , Cálcio , Mitocôndrias , Mitofagia , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Cálcio/metabolismo , Animais , Hemostasia , Homeostase
9.
Nat Commun ; 15(1): 5818, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987265

RESUMO

A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.


Assuntos
Asma , Proteínas de Ciclo Celular , Células Epiteliais , Ferroptose , Proteínas de Membrana Transportadoras , Mitocôndrias , Mitofagia , Fenótipo , Fator de Transcrição TFIIIA , Humanos , Mitocôndrias/metabolismo , Asma/metabolismo , Asma/patologia , Células Epiteliais/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Fator de Transcrição TFIIIA/metabolismo , Fator de Transcrição TFIIIA/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Masculino , Proteínas Quinases/metabolismo , Feminino , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Peroxidação de Lipídeos , Camundongos , Pessoa de Meia-Idade
10.
Aging (Albany NY) ; 16(11): 9334-9349, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834039

RESUMO

Mitophagy is a selective form of autophagy which permits the removal of dysfunctional or excess mitochondria. This occurs as an adaptative response to physiological stressors, such as hypoxia, nutrient deprivation, or DNA damage. Mitophagy is promoted by specific mitochondrial outer membrane receptors, among which are BNIP3 and BNIP3L. The role of mitophagy in cancer is being widely studied, and more specifically in the maintenance of cancer stem cell (CSC) properties, such as self-renewal. Given that CSCs are responsible for treatment failure and metastatic capacity, targeting mitophagy could be an interesting approach for CSC elimination. Herein, we describe a new model system to enrich sub-populations of cancer cells with high basal levels of mitophagy, based on the functional transcriptional activity of BNIP3 and BNIP3L. Briefly, we employed a BNIP3(L)-promoter-eGFP-reporter system to isolate cancer cells with high BNIP3/BNIP3L transcriptional activity by flow cytometry (FACS). The model was validated by using complementary lysosomal and mitophagy-specific probes, as well as the mitochondrially-targeted red fluorescent protein (RFP), namely mt-Keima. High BNIP3/BNIP3L transcriptional activity was accompanied by increases in i) BNIP3/BNIP3L protein levels, ii) lysosomal mass, and iii) basal mitophagy activity. Furthermore, cancer cells with increased BNIP3/BNIP3L transcriptional activity exhibited CSC features, such as greater mammosphere-forming ability and high CD44 levels. To further explore the model, we also analysed other stemness characteristics in MCF7 and MDA-MB-231 breast cancer cell lines, directly demonstrating that BNIP3(L)-high cells were more metabolically active, proliferative, migratory, and drug-resistant, with elevated anti-oxidant capacity. Therefore, high levels of basal mitophagy appear to enhance CSC features.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas de Membrana , Mitofagia , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética
11.
Eur J Pharmacol ; 977: 176743, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38880222

RESUMO

Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.


Assuntos
Proteínas Quinases Ativadas por AMP , Citarabina , Modelos Animais de Doenças , Mitofagia , Proteínas Quinases , Ubiquitina-Proteína Ligases , Animais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Citarabina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Apoptose/efeitos dos fármacos
12.
Bone ; 186: 117146, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38844017

RESUMO

Obesity has become a major global health problem and the effect on bone formation has received increasing attention. However, the interaction between obesity and bone metabolism is complex and still not fully understood. Here, we show that caveolin-1 (Cav1), a membrane scaffold protein involved in regulating a variety of cellular processes, plays a key regulatory role as a bridge connecting obesity and bone metabolism. High-fat diet (HFD)-induced obese C57BL/6J mouse displayed a significant increase in Cav1 expression and lower osteogenic activity; In vitro treatment of osteoblastic MC3T3-E1 cells with 1 mM free fatty acids (FFA) significantly promoted Cav1 expression and PINK1/Parkin regulated mitophagy, but inhibited the expression of osteogenic marker genes. Conversely, reduced expression of the Cav1 gene prevented these effects. Both endogenous oxidative stress and Sirt1 pathway were also significantly reduced after Cav1 knockdown in FFA-treated cells. Finally, Cav1-Sirt1 docking and co-immunoprecipitation results showed that Cav1 interacted with Sirt1 and FFA enhanced the interaction. Taken together, these results suggest that obesity impairs bone development and formation through up-regulation of the Cav1 gene, which lead to inhibition of Sirt1/FOXO1 and Sirt1/PGC-1α signaling pathways through interacting with Sirt1 molecule, and an increase of mitophagy level.


Assuntos
Caveolina 1 , Camundongos Endogâmicos C57BL , Mitofagia , Obesidade , Osteogênese , Transdução de Sinais , Sirtuína 1 , Animais , Caveolina 1/metabolismo , Osteogênese/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/patologia , Sirtuína 1/metabolismo , Camundongos , Masculino , Dieta Hiperlipídica , Linhagem Celular
13.
Cell Death Dis ; 15(6): 462, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38942784

RESUMO

S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.


Assuntos
Calgranulina A , Calgranulina B , Mitocôndrias , Neutrófilos , Sepse , Calgranulina A/metabolismo , Calgranulina A/genética , Neutrófilos/metabolismo , Sepse/patologia , Sepse/metabolismo , Sepse/genética , Humanos , Calgranulina B/metabolismo , Calgranulina B/genética , Mitocôndrias/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Animais , Camundongos , Masculino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Mitofagia , Camundongos Endogâmicos C57BL , Apoptose
14.
Mol Biol Rep ; 51(1): 776, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904879

RESUMO

BACKGROUND: Traumatic hemorrhagic shock (THS) is a complex pathophysiological process resulting in multiple organ failure. Intestinal barrier dysfunction is one of the mechanisms implicated in multiple organ failure. The present study aimed to explore the regulatory role of mitogen-activated protein kinase kinase 3 (MKK3) in THS-induced intestinal injury and to elucidate its potential mechanism. METHODS: Rats were subjected to trauma and hemorrhage to establish a THS animal model. MKK3-targeted lentiviral vectors were injected via the tail vein 72 h before modeling. Twelve hours post-modeling, the mean arterial pressure (MAP) and heart rate (HR) were monitored, and histological injury to the intestine was assessed via H&E staining and transmission electron microscopy. Mitochondrial function and mitochondrial reactive oxygen species (ROS) were evaluated. IEC-6 cells were exposed to hypoxia to mimic intestinal injury following THS in vitro. RESULTS: MKK3 deficiency alleviated intestinal injury and restored mitochondrial function in intestinal tissues from THS-induced rats and hypoxia-treated IEC-6 cells. In addition, MKK3 deficiency promoted Sirt1/PGC-1α-mediated mitochondrial biogenesis and restricted Pink1/Parkin-mediated mitophagy in the injured intestine and IEC-6 cells. Furthermore, the protective effect of MKK3 knockdown against hypoxia-induced mitochondrial damage was strengthened upon simultaneous LC3B/Pink1/Parkin knockdown or weakened upon simultaneous Sirt1 knockdown. CONCLUSION: MKK3 deficiency protected against intestinal injury induced by THS by promoting mitochondrial biogenesis and restricting excessive mitophagy.


Assuntos
Intestinos , MAP Quinase Quinase 3 , Mitocôndrias , Espécies Reativas de Oxigênio , Choque Hemorrágico , Animais , Masculino , Ratos , Linhagem Celular , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase 3/genética , Mitocôndrias/metabolismo , Mitofagia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Choque Hemorrágico/complicações , Choque Hemorrágico/metabolismo , Choque Hemorrágico/genética , Choque Traumático/metabolismo , Choque Traumático/complicações , Choque Traumático/genética
15.
FASEB J ; 38(13): e23701, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38941193

RESUMO

Zearalenone (ZEN) is a mycotoxin known for its estrogen-like effects, which can disrupt the normal physiological function of endometrial cells and potentially lead to abortion in female animals. However, the precise mechanism by which ZEN regulates endometrial function remains unclear. In this study, we found that the binding receptor estrogen receptors for ZEN is extensively expressed across various segments of the uterus and within endometrial cells, and a certain concentration of ZEN treatment reduced the proliferation capacity of goat endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Meanwhile, cell cycle analysis revealed that ZEN treatment leaded to cell cycle arrest in goat EECs and ESCs. To explore the underlying mechanism, we investigated the mitochondrial quality control systems and observed that ZEN triggered excessive mitochondrial fission and disturbed the balance of mitochondrial fusion-fission dynamics, impaired mitochondrial biogenesis, increased mitochondrial unfolded protein response and mitophagy in goat EECs and ESCs. Additionally, ZEN treatment reduced the activities of mitochondrial respiratory chain complexes, heightened the production of hydrogen peroxide and reactive oxygen species, and caused cellular oxidative stress and mitochondrial dysfunction. These results suggest that ZEN has adverse effects on goat endometrium cells by disrupting the mitochondrial quality control system and affecting cell cycle and proliferation. Understanding the underlying molecular pathways involved in ZEN-induced mitochondrial dysfunction and its consequences on cell function will provide critical insights into the reproductive toxicity of ZEN and contribute to safeguarding the health and wellbeing of animals and humans exposed to this mycotoxin.


Assuntos
Proliferação de Células , Endométrio , Cabras , Mitocôndrias , Zearalenona , Animais , Feminino , Endométrio/citologia , Endométrio/metabolismo , Endométrio/efeitos dos fármacos , Zearalenona/toxicidade , Zearalenona/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Cultivadas , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/citologia
16.
J Hazard Mater ; 475: 134855, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38880044

RESUMO

Cadmium (Cd) is a common environmental pollutant, while selenium (Se) can ameliorate heavy metal toxicity. Consequently, this study aimed to investigate the protective effects of Se against Cd-induced hepatocyte injury and its underlying mechanisms. To achieve this, we utilized the Dongdagou-Xinglong cohort, BRL3A cell models, and a rat model exposed to Cd and/or Se. The results showed that Se counteracted liver function injury and the decrease in GPER1 levels caused by environmental Cd exposure, and various methods confirmed that Se could protect against Cd-induced hepatotoxicity both in vivo and in vitro. Mechanistically, Cd caused excessive mitophagy activation, evidenced by the colocalization of LC3B, PINK1, Parkin, P62, and TOMM20. Transfection of BRL3A cells with mt-keima adenovirus indicated that Cd inhibited autophagosome-lysosome fusion, thereby impeding mitophagic flux. Importantly, G1, a specific agonist of GPER1, mitigated Cd-induced mitophagy overactivation and hepatocyte toxicity, whereas G15 exacerbates these effects. Notably, Se supplementation attenuated Cd-induced GPER1 protein reduction and excessive mitophagy activation while facilitating autophagosome-lysosome fusion, thereby restoring mitophagic flux. In conclusion, this study proposed a novel mechanism whereby Se alleviated GPER1-mediated mitophagy and promoted autophagosome-lysosome fusion, thus restoring Cd-induced mitophagic flux damage, and preventing hepatocyte injury.


Assuntos
Cádmio , Doença Hepática Induzida por Substâncias e Drogas , Hepatócitos , Mitofagia , Receptores Acoplados a Proteínas G , Selênio , Animais , Mitofagia/efeitos dos fármacos , Cádmio/toxicidade , Receptores Acoplados a Proteínas G/metabolismo , Masculino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Selênio/farmacologia , Ratos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Linhagem Celular , Ratos Sprague-Dawley , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia
17.
Mol Neurodegener ; 19(1): 49, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890703

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. METHODS: A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. RESULTS: UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. CONCLUSIONS: Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.


Assuntos
Cumarínicos , Animais , Camundongos , Cumarínicos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Retina/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Proteína Sequestossoma-1/metabolismo , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BL , Iodatos/toxicidade
18.
J Cell Mol Med ; 28(12): e18455, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38898772

RESUMO

Cancer-related fatigue (CRF) significantly impacts the quality of life of cancer patients. This study investigates the therapeutic potential of Shenqi Fuzheng injection (SFI) in managing CRF, focusing on its mechanistic action in skeletal muscle. We utilized a CRF mouse model to examine the effects of SFI on physical endurance, monitoring activity levels, swimming times and rest periods. Proteomic analysis of the gastrocnemius muscle was performed using isobaric tags and liquid chromatography-tandem mass spectrometry to map the muscle proteome changes post-SFI treatment. Mitochondrial function in skeletal muscle was assessed via ATP bioluminescence assay. Furthermore, the regulatory role of the hypoxia inducible factor 1 subunit alpha (HIF-1α) signalling pathway in mediating SFI's effects was explored through western blotting. In CRF-induced C2C12 myoblasts, we evaluated cell viability (CCK-8 assay), apoptosis (flow cytometry) and mitophagy (electron microscopy). The study also employed pulldown, luciferase and chromatin immunoprecipitation assays to elucidate the molecular mechanisms underlying SFI's action, particularly focusing on the transcriptional regulation of PINK1 through HIF-1α binding at the PINK1 promoter region. Our findings reveal that SFI enhances physical mobility, reduces fatigue symptoms and exerts protective effects on skeletal muscles by mitigating mitochondrial damage and augmenting antioxidative responses. SFI promotes cell viability and induces mitophagy while decreasing apoptosis, primarily through the modulation of HIF-1α, PINK1 and p62 proteins. These results underscore SFI's efficacy in enhancing mitochondrial autophagy, thereby offering a promising approach for ameliorating CRF. The study not only provides insight into SFI's potential therapeutic mechanisms but also establishes a foundation for further exploration of SFI interventions in CRF management.


Assuntos
Medicamentos de Ervas Chinesas , Fadiga , Subunidade alfa do Fator 1 Induzível por Hipóxia , Mitofagia , Músculo Esquelético , Neoplasias , Ubiquitinação , Animais , Mitofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Ubiquitinação/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fadiga/tratamento farmacológico , Fadiga/metabolismo , Fadiga/etiologia , Masculino , Apoptose/efeitos dos fármacos , Humanos , Proteômica/métodos , Modelos Animais de Doenças , Linhagem Celular
19.
J Cell Mol Med ; 28(11): e18476, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38842136

RESUMO

Osteoarthritis (OA) is a complicated disease that involves apoptosis and mitophagy. MST1 is a pro-apoptotic factor. Hence, decreasing its expression plays an anti-apoptotic effect. This study aims to investigate the protective effect of MST1 inhibition on OA and the underlying processes. Immunofluorescence (IF) was used to detect MST1 expression in cartilage tissue. Western Blot, ELISA and IF were used to analyse the expression of inflammation, extracellular matrix (ECM) degradation, apoptosis and mitophagy-associated proteins. MST1 expression in chondrocytes was inhibited using siRNA and shRNA in vitro and in vivo. Haematoxylin-Eosin, Safranin O-Fast Green and alcian blue staining were used to evaluate the therapeutic effect of inhibiting MST1. This study discovered that the expression of MST1 was higher in OA patients. Inhibition of MST1 reduced inflammation, ECM degradation and apoptosis and enhanced mitophagy in vitro. MST1 inhibition slows OA progression in vivo. Inhibiting MST1 suppressed apoptosis, inflammation and ECM degradation via promoting Parkin-mediated mitophagy and the Nrf2-NF-κB axis. The results suggest that MST1 is a possible therapeutic target for the treatment of osteoarthritis as its inhibition delays the progression of OA through the Nrf2-NF-κB axis and mitophagy.


Assuntos
Apoptose , Condrócitos , Progressão da Doença , Mitofagia , Fator 2 Relacionado a NF-E2 , NF-kappa B , Osteoartrite , Transdução de Sinais , Ubiquitina-Proteína Ligases , Animais , Humanos , Masculino , Camundongos , Apoptose/genética , Condrócitos/metabolismo , Condrócitos/patologia , Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Inflamação/patologia , Inflamação/metabolismo , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular , Mitofagia/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
20.
Life Sci Alliance ; 7(9)2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38906677

RESUMO

Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.


Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Modelos Animais de Doenças , Demência Frontotemporal , Proteína 1 Associada a ECH Semelhante a Kelch , Mitocôndrias , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fenótipo , Transdução de Sinais , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Mitocôndrias/metabolismo , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Espécies Reativas de Oxigênio/metabolismo , Mitofagia/genética , Fumarato de Dimetilo/farmacologia , Masculino
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