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1.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 403-408, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402260

RESUMO

SIRT3, SIRT4 and SIRT5 are located in mitochondria and also known as mitochondrial sirtuins. They play important roles in regulating many cellular functions including cell survival, cell cycle or apoptosis, DNA repair and metabolism. Mitochondrial sirtuins are involved in the protection of mitochondrial integrity and energy metabolism under stress regulating the expression of neurotransmitter receptors, neurotrophins, extracellular matrix proteins and various transcription factors, thus involved in epileptogenesis triggered by both genetic or acquired factors. Here we review research progress on the actions of mitochondrial sirtuin in epilepsy; and discuss the challenges and perspectives of mitochondrial sirtuin as a potential therapeutic target for epilepsy.


Assuntos
Epilepsia , Sirtuína 3 , Sirtuínas , Apoptose , Epilepsia/genética , Humanos , Mitocôndrias/genética
2.
FASEB J ; 35(9): e21752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369602

RESUMO

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1ß coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1ß [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.


Assuntos
Tecido Adiposo/metabolismo , Mitocôndrias/genética , Proteínas Nucleares/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/genética , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Metabolismo Energético/genética , Heterozigoto , Resistência à Insulina/genética , Masculino , Camundongos , Obesidade/genética , Termogênese/genética , Transcriptoma/genética
3.
FASEB J ; 35(9): e21814, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369624

RESUMO

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mitocôndrias/genética , Chaperonas Moleculares/genética , Monoéster Fosfórico Hidrolases/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Proteína Supressora de Tumor p53/genética , Adaptação Biológica/genética , Apoptose/genética , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glucose/genética , Células Hep G2 , Homeostase/genética , Humanos , Potencial da Membrana Mitocondrial/genética , Estresse Fisiológico/genética , Ativação Transcricional/genética
4.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445202

RESUMO

The yeast Saccharomyces cerevisiae is one of the most widely used model organisms for investigating various aspects of basic cellular functions that are conserved in human cells. This organism, as well as human cells, can modulate its metabolism in response to specific growth conditions, different environmental changes, and nutrient depletion. This adaptation results in a metabolic reprogramming of specific metabolic pathways. Mitochondrial carriers play a fundamental role in cellular metabolism, connecting mitochondrial with cytosolic reactions. By transporting substrates across the inner membrane of mitochondria, they contribute to many processes that are central to cellular function. The genome of Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, most of which have been functionally characterized. The aim of this review is to describe the role of the so far identified yeast mitochondrial carriers in cell metabolism, attempting to show the functional connections between substrates transport and specific metabolic pathways, such as oxidative phosphorylation, lipid metabolism, gluconeogenesis, and amino acids synthesis. Analysis of the literature reveals that these proteins transport substrates involved in the same metabolic pathway with a high degree of flexibility and coordination. The understanding of the role of mitochondrial carriers in yeast biology and metabolism could be useful for clarifying unexplored aspects related to the mitochondrial carrier network. Such knowledge will hopefully help in obtaining more insight into the molecular basis of human diseases.


Assuntos
Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico Ativo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
6.
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
7.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360765

RESUMO

Mitochondria, often referred to as the powerhouses of cells, are vital organelles that are present in almost all eukaryotic organisms, including humans. They are the key energy suppliers as the site of adenosine triphosphate production, and are involved in apoptosis, calcium homeostasis, and regulation of the innate immune response. Abnormalities occurring in mitochondria, such as mitochondrial DNA (mtDNA) mutations and disturbances at any stage of mitochondrial RNA (mtRNA) processing and translation, usually lead to severe mitochondrial diseases. A fundamental line of investigation is to understand the processes that occur in these organelles and their physiological consequences. Despite substantial progress that has been made in the field of mtRNA processing and its regulation, many unknowns and controversies remain. The present review discusses the current state of knowledge of RNA processing in human mitochondria and sheds some light on the unresolved issues.


Assuntos
Mitocôndrias/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Humanos , Mitocôndrias/genética , RNA Mitocondrial/genética
8.
Nat Commun ; 12(1): 4920, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389715

RESUMO

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.


Assuntos
Mesotelioma Maligno/genética , Oncogenes/genética , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Animais , Asbestos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mesotelioma Maligno/induzido quimicamente , Mesotelioma Maligno/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Naftiridinas/farmacologia , Polirribossomos/efeitos dos fármacos , Polirribossomos/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas
9.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34312306

RESUMO

Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type in mice. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single-cell mRNA sequencing (scRNAseq) could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that the proteome encompassing these nuclear-encoded mitochondrial genes and obtained from microdissected brain tissue segregated the hippocampus, striatum, and cortex from each other. Nuclear-encoded mitochondrial transcripts could only segregate cell types and brain regions when the analysis was performed at the single-cell level. In fact, single-cell mitochondrial transcriptomes were able to distinguish glutamatergic and distinct types of GABAergic neurons from one another. Within these cell categories, unique SLC25A transporters were able to identify distinct cell subpopulations. Our results demonstrate heterogeneous mitochondrial composition across brain regions and cell types. We postulate that mitochondrial heterogeneity influences regional and cell type-specific mechanisms in health and disease.


Assuntos
Genes Mitocondriais , Neurônios , Animais , Núcleo Celular , Hipocampo , Camundongos , Mitocôndrias/genética , Neurônios/metabolismo
10.
Nat Commun ; 12(1): 4284, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257281

RESUMO

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.


Assuntos
Transtorno do Espectro Autista/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transtorno do Espectro Autista/genética , Citosol/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética
11.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199378

RESUMO

Iron-sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe-S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two in eukaryotes (CIA and ISC pathways), the iron-sulfur cluster (ISC) pathway serves as the central mechanism for providing 2Fe-2S clusters, directly and indirectly, throughout the entire cell in eukaryotes. Proteins central to the eukaryotic ISC cluster assembly complex include the cysteine desulfurase, a cysteine desulfurase accessory protein, the acyl carrier protein, the scaffold protein and frataxin (in humans, NFS1, ISD11, ACP, ISCU and FXN, respectively). Recent molecular details of this complex (labeled NIAUF from the first letter from each ISC protein outlined earlier), which exists as a dimeric pentamer, have provided real structural insight into how these partner proteins arrange themselves around the cysteine desulfurase, the core dimer of the (NIAUF)2 complex. In this review, we focus on both frataxin and the scaffold within the human, fly and yeast model systems to provide a better understanding of the biophysical characteristics of each protein alone and within the FXN/ISCU complex as it exists within the larger NIAUF construct. These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe-S cluster assembly.


Assuntos
Proteínas de Ligação ao Ferro/genética , Proteínas Ferro-Enxofre/genética , Ferro/metabolismo , Enxofre/metabolismo , Liases de Carbono-Enxofre/genética , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/ultraestrutura , Ligação Proteica/genética
12.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199596

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Mitocôndrias/genética , Obesidade/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adipócitos/metabolismo , Tecido Adiposo Branco/fisiologia , Restrição Calórica , Humanos , Lipogênese/genética , Mitocôndrias/metabolismo , Obesidade/patologia , Biogênese de Organelas
13.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209978

RESUMO

Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Doenças Neurodegenerativas/genética , Animais , Citosol/metabolismo , Humanos , Mutação , Doenças Neurodegenerativas/imunologia
14.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299348

RESUMO

Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modelling these disorders is challenging as many non-human models of mitochondrial disease do not completely recapitulate human phenotypes for known disease genes. Additionally, access to disease-relevant cell or tissue types from patients is often limited. To overcome these difficulties, many groups have turned to human pluripotent stem cells (hPSCs) to model mitochondrial disease for both nuclear-DNA (nDNA) and mitochondrial-DNA (mtDNA) contexts. Leveraging the capacity of hPSCs to differentiate into clinically relevant cell types, these models permit both detailed investigation of cellular pathomechanisms and validation of promising treatment options. Here we catalogue hPSC models of mitochondrial disease that have been generated to date, summarise approaches and key outcomes of phenotypic profiling using these models, and discuss key criteria to guide future investigations using hPSC models of mitochondrial disease.


Assuntos
Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Células-Tronco Pluripotentes/patologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , DNA Mitocondrial/genética , Humanos , Fenótipo
15.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199142

RESUMO

Metabolism is the central engine of living organisms as it provides energy and building blocks for many essential components of each cell, which are required for specific functions in different tissues. Mitochondria are the main site for energy production in living organisms and they also provide intermediate metabolites required for the synthesis of other biologically relevant molecules. Such cellular processes are finely tuned at different levels, including allosteric regulation, posttranslational modifications, and transcription of genes encoding key proteins in metabolic pathways. Peroxisome proliferator activated receptor γ coactivator 1 (PGC1) proteins are transcriptional coactivators involved in the regulation of many cellular processes, mostly ascribable to metabolic pathways. Here, we will discuss some aspects of the cellular processes regulated by PGC1s, bringing up some examples of their role in mitochondrial and cellular metabolism, and how metabolic regulation in mitochondria by members of the PGC1 family affects the immune system. We will analyze how PGC1 proteins are regulated at the transcriptional and posttranslational level and will also examine other regulators of mitochondrial metabolism and the related cellular functions, considering approaches to identify novel mitochondrial regulators and their role in physiology and disease. Finally, we will analyze possible therapeutical perspectives currently under assessment that are applicable to different disease states.


Assuntos
Metabolismo Energético , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Redes e Vias Metabólicas , Especificidade de Órgãos , Termogênese
16.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200828

RESUMO

Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health and disease so that therapies can be developed to maintain the homeostatic balance of mitochondrial dynamics. Mitochondrial disorders are multisystemic and characterized by complex and variable clinical pathologies. The dynamics of mitochondria in mitochondrial disorders is thus worthy of investigation. Therefore, in this study, we performed a comprehensive analysis of mitochondrial dynamics in ten patient-derived fibroblasts containing different mutations and deletions associated with various mitochondrial disorders. Our results suggest that the most predominant morphological signature for mitochondria in the diseased state is fragmentation, with eight out of the ten cell lines exhibiting characteristics consistent with fragmented mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in cell lines with a wide array of developmental and mitochondrial disorders. A more thorough analysis of the correlations between mitochondrial dynamics, mitochondrial genome perturbations, and bioenergetic dysfunction will aid in identifying unique morphological signatures of various mitochondrial disorders in the future.


Assuntos
Deficiências do Desenvolvimento/patologia , Metabolismo Energético , Fibroblastos/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Mutação , Estudos de Casos e Controles , Deficiências do Desenvolvimento/etiologia , Fibroblastos/metabolismo , Homeostase , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/etiologia
17.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202179

RESUMO

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along "Western diet" feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression.


Assuntos
Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Autofagia , Ésteres do Colesterol/metabolismo , Biologia Computacional/métodos , Suscetibilidade a Doenças , Fibrose , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Mitocôndrias/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , Estresse Oxidativo , Triglicerídeos/metabolismo
18.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202229

RESUMO

Alveolar epithelial cell (AEC) mitochondrial (mt) DNA damage and fibrotic monocyte-derived alveolar macrophages (Mo-AMs) are implicated in the pathobiology of pulmonary fibrosis. We showed that sirtuin 3 (SIRT3), a mitochondrial protein regulating cell fate and aging, is deficient in the AECs of idiopathic pulmonary fibrosis (IPF) patients and that asbestos- and bleomycin-induced lung fibrosis is augmented in Sirt3 knockout (Sirt3-/-) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (Sirt3Tg) protects mice from asbestos-induced pulmonary fibrosis by mitigating lung mtDNA damage and Mo-AM recruitment. Crocidolite asbestos (100 µg/50 µL) or control was instilled intratracheally in C57Bl6 (Wild-Type) mice or Sirt3Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3Tg mice were protected from asbestos-induced pulmonary fibrosis and had diminished lung mtDNA damage and Mo-AM recruitment. Further, pharmacologic SIRT3 inducers (i.e., resveratrol, viniferin, and honokiol) each diminish oxidant-induced AEC mtDNA damage in vitro and, in the case of honokiol, protection occurs in a SIRT3-dependent manner. We reason that SIRT3 preservation of AEC mtDNA is a novel therapeutic focus for managing patients with IPF and other types of pulmonary fibrosis.


Assuntos
Asbestos/efeitos adversos , Dano ao DNA , Expressão Gênica , Fibrose Pulmonar Idiopática/etiologia , Mitocôndrias/genética , Monócitos/metabolismo , Sirtuína 3/genética , Animais , Biomarcadores , DNA Mitocondrial , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Monócitos/imunologia , Monócitos/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo
19.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204357

RESUMO

Heme biosynthesis is essential for almost all living organisms. Despite its conserved function, the pathway's enzymes can be located in a remarkable diversity of cellular compartments in different organisms. This location does not always reflect their evolutionary origins, as might be expected from the history of their acquisition through endosymbiosis. Instead, the final subcellular localization of the enzyme reflects multiple factors, including evolutionary origin, demand for the product, availability of the substrate, and mechanism of pathway regulation. The biosynthesis of heme in the apicomonad Chromera velia follows a chimeric pathway combining heme elements from the ancient algal symbiont and the host. Computational analyses using different algorithms predict complex targeting patterns, placing enzymes in the mitochondrion, plastid, endoplasmic reticulum, or the cytoplasm. We employed heterologous reporter gene expression in the apicomplexan parasite Toxoplasma gondii and the diatom Phaeodactylum tricornutum to experimentally test these predictions. 5-aminolevulinate synthase was located in the mitochondria in both transfection systems. In T. gondii, the two 5-aminolevulinate dehydratases were located in the cytosol, uroporphyrinogen synthase in the mitochondrion, and the two ferrochelatases in the plastid. In P. tricornutum, all remaining enzymes, from ALA-dehydratase to ferrochelatase, were placed either in the endoplasmic reticulum or in the periplastidial space.


Assuntos
Alveolados/fisiologia , Apicomplexa/metabolismo , Diatomáceas/metabolismo , Heme/metabolismo , Redes e Vias Metabólicas , Sequência de Aminoácidos , Transporte Biológico , Evolução Molecular , Regulação Enzimológica da Expressão Gênica , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
20.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204592

RESUMO

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Mitocôndrias/metabolismo , NADH Desidrogenase/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , NADH Desidrogenase/genética , Transporte Proteico , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
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