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1.
Anal Chim Acta ; 1178: 338847, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34482880

RESUMO

Photodynamic therapy has been generally developed and approved as a promising theranostic technique in recent years, which requires photosensitizers to bear high efficiency of reactive oxygen species production, precisely targeting ability and excellent biocompatibility. The real-time monitoring the microenvironments such as viscosity dynamic involved in mitophagy mediated by photodynamic therapy is significantly important to understand therapeutic process but barely reported. In this work, a pyridinium-functionalized triphenylamine derivative, (E)-4-(2-(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl)vinyl)-1-methylpyridin-1-ium iodide (Mito-I), was exploited as photosensitizer for mitochondria-targeted photodynamic therapy and as fluorescent probe for imaging the mitochondrial viscosity dynamic during mitophagy simultaneously. The results indicated that the additional phenyl ring in Mito-I was beneficial to promote its efficiency of singlet oxygen production. The excellent capability of targeting mitochondria and singlet oxygen generation allowed Mito-I for the specifically mitochondria-targeted photodynamic therapy. Moreover, Mito-I displayed off-on fluorescence response to viscosity with high selectivity and sensitivity. The observed enhancement in fluorescence intensity of Mito-I revealed the increasingly mitochondrial viscosity during mitophagy mediated by the photodynamic therapy of Mito-I. As a result, this work presents a rare example to realize the mitochondria-targeting photodynamic therapy as well as the real-time monitoring viscosity dynamic during mitophagy, which is of great importance for the basic medical research involved in photodynamic therapy.


Assuntos
Mitofagia , Fotoquimioterapia , Mitocôndrias , Fármacos Fotossensibilizantes/farmacologia , Viscosidade
2.
Am J Physiol Regul Integr Comp Physiol ; 321(4): R625-R633, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34494473

RESUMO

Mitochondria are the main organelles for mammalian energy metabolism and have been implicated in the regulation of germ cell maintenance and spermatogenesis. However, little is known about the changes in the mitochondria of the testis of seasonal breeders. Here, we characterized the seasonal changes in the mitochondria in the testis of the wild ground squirrels. Increased testicle weight, seminiferous tubule diameter, and sperm count were observed in the wild ground squirrels at the breeding season. RNA-seq analysis of the wild ground squirrel testes revealed that mitochondrial-related genes were expressed differentially between the breeding and nonbreeding seasons. Immunohistochemical staining showed that key mitophagy factors including PINK1, MFN2, and PARKIN were highly expressed in various cell types of testis during the breeding season. In addition, the abundance and enzymatic activities of mitochondrial-localized antioxidative enzymes superoxide dismutase 2 (SOD2) and Catalase were decreased in the testis during the breeding season, suggesting a tightly controlled redox balance at least partially facilitated by mitophagy during the seasonal breeding. Taken together, our study reveals that mitochondrial autophagy and oxidative stress may be implicated in the seasonal reproductive recrudescence of the wild ground squirrels, which deepens our understanding of the mitochondrial regulation of seasonal reproductivity in wildlife and provides new insights into the development of potential therapeutic interventions of male infertility.


Assuntos
Cruzamento , Metabolismo Energético , Mitocôndrias/metabolismo , Mitofagia , Estresse Oxidativo , Sciuridae/metabolismo , Estações do Ano , Testículo/metabolismo , Animais , Catalase/genética , Catalase/metabolismo , Masculino , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Tamanho do Órgão , Sciuridae/genética , Espermatogênese , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Transcriptoma , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
Anal Chem ; 93(37): 12786-12792, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34505518

RESUMO

Mitochondrial pH (pHmito) is intimately related to mitochondrial function, and aberrant values for pHmito are linked to several disease states. We report the design, synthesis, and application of mitokyne 1-the first small molecule pHmito sensor for stimulated Raman scattering (SRS) microscopy. This ratiometric probe can determine subtle changes in pHmito in response to external stimuli and the inhibition of both the electron transport chain and ATP synthase with small molecule inhibitors. In addition, 1 was also used to monitor mitochondrial dynamics in a time-resolved manner with subcellular spatial resolution during mitophagy providing a powerful tool for dissecting the molecular and cell biology of this critical organelle.


Assuntos
Mitocôndrias , Mitofagia , Concentração de Íons de Hidrogênio , Microscopia , Análise Espectral Raman
4.
Life Sci ; 284: 119906, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34478761

RESUMO

The present study was performed to investigate the effects of Cd exposure on lipid metabolism and mitochondrial dysfunction and to explore the role of mitophagy in Cd-induced dysregulation of lipid metabolism in chicken embryo liver tissues and hepatocytes. To this end, seven-day-old chicken embryos were exposed to different concentrations of Cd for 7 days, and primary chicken embryo hepatocytes were treated with Cd at four different concentrations for 6 h. Furthermore, the mitophagy inhibitor cyclosporine A (CsA) was used to investigate the role of mitophagy in Cd-induced disruption of lipid metabolism. Lipid accumulation, the expression levels of genes involved in lipid metabolism, mitochondrial dysfunction, and mitophagy were measured. The results demonstrated that Cd exposure increases hepatic triglyceride (TG) accumulation and the expression levels of lipogenic genes while decreasing those of lipolytic genes. Furthermore, Cd exposure was observed to alter mitochondrial morphology in terms of reduced size, excessive mitochondrial damage, and the formation of mitophagosomes. The co-localization of lysosome-associated membrane glycoprotein 2 and LC3 puncta was significantly increased in primary chicken embryo hepatocytes after Cd exposure. Moreover, Cd exposure increased LC3, PINK1, and Parkin protein expression levels. CsA effectively alleviated Cd-induced mitochondrial dysfunction, blocked mitochondrial membrane potential collapse, and suppressed PINK1/Parkin-mediated mitophagy. Furthermore, CsA treatment reversed the Cd-induced TG accumulation in liver tissues but further increased it in hepatocytes. Taken together, our findings demonstrate (for the first time) the importance of mitochondrial dysfunction and mitophagy via the PINK1/Parkin pathway in Cd-induced disruption of lipid metabolism.


Assuntos
Cádmio/toxicidade , Metabolismo dos Lipídeos , Fígado/metabolismo , Mitocôndrias Hepáticas/patologia , Mitofagia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Embrião de Galinha , Ciclosporina/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/embriologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/ultraestrutura , Mitofagia/efeitos dos fármacos , Modelos Biológicos
5.
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
6.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360946

RESUMO

The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca2+ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy-the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.


Assuntos
Envelhecimento/metabolismo , Mitocôndrias Musculares/metabolismo , Dinâmica Mitocondrial , Mitofagia , Sarcopenia/metabolismo , Animais , Humanos , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo
7.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360945

RESUMO

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.


Assuntos
Autofagia , COVID-19/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/virologia , Animais , Autofagia/efeitos dos fármacos , COVID-19/tratamento farmacológico , Humanos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Viroses/tratamento farmacológico , Viroses/metabolismo
8.
Stem Cell Res Ther ; 12(1): 452, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380561

RESUMO

Mitophagy is a specific autophagic phenomenon in which damaged or redundant mitochondria are selectively cleared by autophagic lysosomes. A decrease in mitophagy can accelerate the aging process. Mitophagy is related to health and longevity and is the key to protecting stem cells from metabolic stress damage. Mitophagy decreases the metabolic level of stem cells by clearing active mitochondria, so mitophagy is becoming increasingly necessary to maintain the regenerative capacity of old stem cells. Stem cell senescence is the core problem of tissue aging, and tissue aging occurs not only in stem cells but also in transport amplifying cell chambers and the stem cell environment. The loss of the autophagic ability of stem cells can cause the accumulation of mitochondria and the activation of the metabolic state as well as damage the self-renewal ability and regeneration potential of stem cells. However, the claim remains controversial. Mitophagy is an important survival strategy against nutrient deficiency and starvation, and mitochondrial function and integrity may affect the viability, proliferation and differentiation potential, and longevity of normal stem cells. Mitophagy can affect the health and longevity of the human body, so the number of studies in this field has increased, but the mechanism by which mitophagy participates in stem cell development is still not fully understood. This review describes the potential significance of mitophagy in stem cell developmental processes, such as self-renewal, differentiation and aging. Through this work, we discovered the role and mechanism of mitophagy in different types of stem cells, identified novel targets for killing cancer stem cells and curing cancer, and provided new insights for future research in this field.


Assuntos
Mitocôndrias , Mitofagia , Autofagia , Humanos , Lisossomos/metabolismo , Células-Tronco/metabolismo
9.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360883

RESUMO

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Suplementos Nutricionais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Valeratos/farmacologia , Adenocarcinoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo
10.
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
11.
ACS Chem Neurosci ; 12(16): 3049-3059, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34340312

RESUMO

Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown. Mitophagy is a quality-control mechanism that selectively targets damaged mitochondria for degradation. The goal of this study was to determine if KU-596 therapy improved DPN, mtBE, and mitophagy in an Hsp70- and Txnip-dependent manner. Mito-QC (MQC) mice express a mitochondrially targeted mCherry-GFP fusion protein that enables visualizing mitophagy. Diabetic MQC, MQC × Hsp70 knockout (KO), and MQC × Txnip KO mice developed sensory and nerve conduction dysfunctions consistent with the onset of DPN. KU-596 therapy improved these measures, and this was dependent on Hsp70 but not Txnip. In MQC mice, diabetes decreased mtBE and increased mitophagy and KU-596 treatment reversed these effects. In contrast, KU-596 was unable to improve mtBE and decrease mitophagy in MQC × Hsp70 and MQC × Txnip KO mice. These data suggest that Txnip is not necessary for the development of the sensory symptoms and mitochondrial dysfunction induced by diabetes. KU-596 therapy may improve mitochondrial tolerance to diabetic stress to decrease mitophagic clearance in an Hsp70- and Txnip-dependent manner.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Animais , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Metabolismo Energético , Proteínas de Choque Térmico HSP70/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mitofagia , Células Receptoras Sensoriais/metabolismo , Tiorredoxinas/metabolismo
12.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34340748

RESUMO

Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Mitofagia/genética , Doença de Parkinson/fisiopatologia , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mitofagia/efeitos dos fármacos , Mutação , Doença de Parkinson/genética
13.
Biomolecules ; 11(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34439810

RESUMO

Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.


Assuntos
Injúria Renal Aguda/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Apoptose/genética , Ácidos Graxos/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial , Mitofagia/genética , NADPH Oxidase 1/genética , NADPH Oxidase 1/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação Oxidativa , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
14.
Life Sci ; 284: 119876, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389405

RESUMO

Mitochondria are biosynthetic, bioenergetic, and signaling organelles which are critical for physiological adaptations and cellular stress responses to the environment. Various endogenous and environmental stress affects critical processes in mitochondrial homeostasis such as oxidative phosphorylation, biogenesis, mitochondrial redox system which leads to the formation of reactive oxygen species (ROS) and free radicals. The state of function of the mitochondrion is particularly dependent on the dynamic balance between mitochondrial biogenesis, fusion and fission, and degradation of damaged mitochondria by mitophagy. Increasing evidence has suggested a prominent role of mitochondrial dysfunction in the onset and progression of various lung pathologies, ranging from acute to chronic disorders. In this comprehensive review, we discuss the emerging findings of multifaceted regulations of mitochondrial dynamics and mitophagy in normal lung homeostasis as well as the prominence of mitochondrial dysfunction as a determining factor in different lung disorders such as lung cancer, COPD, IPF, ALI/ARDS, BPD, and asthma. The review will contribute to the existing understanding of critical molecular machinery regulating mitochondrial dynamic state during these pathological states. Furthermore, we have also highlighted various molecular checkpoints involved in mitochondrial dynamics, which may serve as hopeful therapeutic targets for the development of potential therapies for these lung disorders.


Assuntos
Pneumopatias/metabolismo , Dinâmica Mitocondrial , Mitofagia , Animais , Humanos , Modelos Biológicos
15.
Cytogenet Genome Res ; 161(6-7): 297-304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34433164

RESUMO

Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD+ depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD+ and mitophagy may shed light on potential therapeutic strategies for the WS patients.


Assuntos
Envelhecimento/genética , Dano ao DNA , Mitocôndrias/genética , Mitofagia/genética , Células-Tronco/metabolismo , Síndrome de Werner/genética , Animais , Senescência Celular/genética , Humanos , Mitocôndrias/metabolismo , Telômero/genética , Telômero/metabolismo , Síndrome de Werner/metabolismo , Síndrome de Werner/patologia
16.
Cells ; 10(8)2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34440765

RESUMO

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.


Assuntos
Autofagia , COVID-19/fisiopatologia , Sarcoidose/fisiopatologia , COVID-19/enzimologia , Genômica , Humanos , Mitofagia , Proteínas Serina-Treonina Quinases , Sarcoidose/enzimologia , Sequenciamento Completo do Exoma
17.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445125

RESUMO

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.


Assuntos
Autofagia/genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Resistência à Insulina/genética , Insulina/genética , MicroRNAs/genética , Transdução de Sinais/genética , Células Cultivadas , Regulação para Baixo/genética , Células-Tronco Embrionárias/patologia , Humanos , Mitocôndrias/genética , Mitofagia/genética , Neurônios/patologia
18.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445246

RESUMO

The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias Hematológicas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Mitofagia , Animais , Carcinogênese/patologia , Diferenciação Celular , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Mitocôndrias/patologia
19.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445360

RESUMO

Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.


Assuntos
Flavonoides/uso terapêutico , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/prevenção & controle , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Citoproteção/efeitos dos fármacos , Flavonoides/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Medicina de Precisão/métodos , Prognóstico
20.
Theriogenology ; 174: 160-168, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34455243

RESUMO

Vitrification is an effective technique for fertility preservation, but is known to lead to mitochondrial dysfunction in porcine oocytes. Mitophagy is induced to rebalance mitochondrial function, a process in which reactive oxygen species (ROS) plays a role. In this study, vitrified-warmed porcine oocytes were incubated for 4 h with the oxidant AAPH or antioxidant α-tocopherol to alter ROS levels. A series of tests suggested that vitrification damaged mitochondrial structure and caused dysfunction, including blurred mitochondrial cristae, decreased mitochondrial membrane potential, decreased mtDNA copy number and increased ROS generation. This dysfunction resulted in mitophagy and the loss of embryonic developmental potential. Incubation with AAPH or α-tocopherol altered mitochondrial function and mitophagy flux status in vitrified oocytes. The PINK1/Parkin pathway was involved in oxidative stress regulation in vitrified oocytes. Under AAPH-induced oxidative stress, increased fluorescence intensity of Parkin, increased expression of PINK1, Parkin, and LC3B-II, and decreased expression of MFN2 and p62 were observed, whereas the opposite effects were induced under α-tocopherol treatment. The inhibition of ROS by α-tocopherol benefitted mitochondrial homeostasis and alleviated PINK1/Parkin-mediated mitophagy, resulting in the recovery of embryonic developmental potential in vitrified porcine oocytes. Therefore, this study provides a new mechanism for the application of antioxidants to aid the cryopreservation of porcine oocytes.


Assuntos
Mitocôndrias , Mitofagia , Animais , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Oócitos/metabolismo , Estresse Oxidativo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Suínos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
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