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2.
Life Sci Alliance ; 6(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36283702

RESUMO

Most mitochondrial proteins are encoded by nuclear genes, synthetized in the cytosol and targeted into the organelle. To characterize the spatial organization of mitochondrial gene products in zebrafish (Danio rerio), we sequenced RNA from different cellular fractions. Our results confirmed the presence of nuclear-encoded mRNAs in the mitochondrial fraction, which in unperturbed conditions, are mainly transcripts encoding large proteins with specific properties, like transmembrane domains. To further explore the principles of mitochondrial protein compartmentalization in zebrafish, we quantified the transcriptomic changes for each subcellular fraction triggered by the chchd4a -/- mutation, causing the disorders in the mitochondrial protein import. Our results indicate that the proteostatic stress further restricts the population of transcripts on the mitochondrial surface, allowing only the largest and the most evolutionary conserved proteins to be synthetized there. We also show that many nuclear-encoded mitochondrial transcripts translated by the cytosolic ribosomes stay resistant to the global translation shutdown. Thus, vertebrates, in contrast to yeast, are not likely to use localized translation to facilitate synthesis of mitochondrial proteins under proteostatic stress conditions.


Assuntos
Genes Mitocondriais , Peixe-Zebra , Animais , Peixe-Zebra/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , RNA Mensageiro/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas Nucleares/genética
3.
Biochem Biophys Res Commun ; 600: 44-50, 2022 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-35182974

RESUMO

The heat shock transcription factor HSF1 regulates the inducible Hsp gene transcription, whereas HSF2 is involved in the constitutive transcription. HSFs can work for the non-heat shock genes transcription in a case-specific manner to facilitate normal cellular functions. Here, we demonstrate that HSF2 acts as an upstream regulator of heat shock-induced autophagy response in a rat histiocytoma. The heat-induced HSF2 transactivates the B-cell translocation gene-2 (BTG2) transcription, and the latter acts as a transcriptional coactivator for superoxide dismutase (SOD2). The altered HSF2 promoter occupancy on the BTG2 promoter enhances BTG2 transcription. Since SOD2 regulation is linked to mitochondrial redox sensing, HSF2 appears to act as a redox sensor in deciding the cell fate. The HSF2 shRNA or NFE2L2/BTG2 siRNA treatments have interfered with the autophagy response. We demonstrate that HSF2 is an upstream activator of autophagy response, and the HSF2-BTG2-SOD2 axis acts as a switch between the non-selective (micro/macro) and selective (chaperone-mediated) autophagy.


Assuntos
Proteínas de Ligação a DNA , Proteínas Imediatamente Precoces , Animais , Autofagia , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , RNA Interferente Pequeno , Ratos , Superóxido Dismutase/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor
5.
PLoS Genet ; 14(11): e1007743, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30457989

RESUMO

Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life-essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases.

6.
Eur J Neurosci ; 45(4): 528-535, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27859782

RESUMO

Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter (MCU), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1Y431 * mutant zebrafish (Danio rerio) via rescue of mitochondrial respiratory chain function. In contrast, genetic inactivation of the voltage dependent anion channel 1 (VDAC1), located in the outer mitochondrial membrane, did not rescue dopaminergic neurons in PINK1 deficient D. rerio. Subsequent gene expression studies revealed specific upregulation of the mcu regulator micu1 in pink1Y431 * mutant zebrafish larvae and inactivation of micu1 also results in rescue of dopaminergic neurons. The functional consequences of PINK1 deficiency and modified MCU activity were confirmed using a dynamic in silico model of Ca2+ triggered mitochondrial activity. Our data suggest modulation of MCU-mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy in PINK1 mutant PD.


Assuntos
Canais de Cálcio/genética , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/genética , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/genética , Regulação para Cima , Canal de Ânion 1 Dependente de Voltagem/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Peixe-Zebra
7.
Biochem Biophys Res Commun ; 417(1): 43-8, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22120629

RESUMO

Glutathione (GSH) serves as an important anti-oxidant in the brain by scavenging harmful reactive oxygen species that are generated during different molecular processes. The GSH level in the brain provides indirect information on oxidative stress of the brain. We report in vivo detection of GSH non-invasively from various brain regions (frontal cortex, parietal cortex, hippocampus and cerebellum) in bilateral hemispheres of healthy male and female subjects and from bi-lateral frontal cortices in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). All AD patients who participated in this study were on medication with cholinesterase inhibitors. Healthy young male (age 26.4±3.0) and healthy young female (age 23.6±2.1) subjects have higher amount of GSH in the parietal cortical region and a specific GSH distribution pattern (parietal cortex>frontal cortex>hippocampus ~ cerebellum) has been found. Overall mean GSH content is higher in healthy young female compared to healthy young male subjects and GSH is distributed differently in two hemispheres among male and female subjects. In both young female and male subjects, statistically significant (p=0.02 for young female and p=0.001 for young male) difference in mean GSH content is found when compared between left frontal cortex (LFC) and right frontal cortex (RFC). In healthy young female subjects, we report statistically significant positive correlation of GSH content between RFC and LFC (r=0.641, p=0.004) as well as right parietal cortex (RPC) and left parietal cortex (LPC) (r=0.797, p=0.000) regions. In healthy young male subjects, statistically significant positive correlation of GSH content was observed between LFC and LPC (r=0.481, p=0.032) regions. This statistical analysis implicates that in case of a high GSH content in LPC of a young male, his LFC region would also contain high GSH and vice versa. The difference in mean of GSH content between healthy young female control and female AD patients in RFC region (p=0.003) and difference in mean of GSH content between healthy young male control and male AD patients (p=0.05) in LFC region is found to be statistically significant. It is the first scientific report correlating alteration (in selective brain regions) of GSH level with clinical status of male and female subjects using non-invasive imaging technique.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Glutationa/metabolismo , Imageamento por Ressonância Magnética/métodos , Estresse Oxidativo , Biomarcadores/metabolismo , Química Encefálica , Feminino , Glutationa/análise , Humanos , Masculino
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