RESUMO
Pentatricopeptide repeat proteins are involved in mitochondrial both transcriptional and posttranscriptional regulation. Schizosaccharomyces pombe Ppr2 is a general mitochondrial translation factor that plays a critical role in the synthesis of all mitochondrial DNA-encoded oxidative phosphorylation subunits, which are essential for mitochondrial respiration. Our previous analysis showed that ppr2 deletion resulted in increased expression of iron uptake genes and caused ferroptosis-like cell death in S. pombe. In the present work, we showed that deletion of ppr2 reduced viability on glycerol- and galactose-containing media.Php4 is a transcription repressor that regulates iron homeostasis in fission yeast. We found that in the ppr2 deletion strain, Php4 was constitutively active and accumulated in the nucleus in the stationary phase. We also found that deletion of ppr2 decreased the ferroptosis-related protein Gpx1 in the mitochondria. Overexpression of Gpx1 improves the viability of Δppr2 cells. We showed that the deletion of ppr2 increased the production of ROS, downregulated heme synthesis and iron-sulfur cluster proteins, and induced stress proteins. Finally, we observed the nuclear accumulation of Pap1-GFP and Sty1-GFP, suggesting that Sty1 and Pap1 in response to cellular stress in the ppr2 deletion strain. These results suggest thatppr2 deletion may cause mitochondrial dysfunction, which is likely to lead to iron-sensing defect and iron starvation response, resulting in perturbation of iron homeostasis and increased hydroxyl radical production. The increased hydroxyl radical production triggers cellular responses in theppr2 deletion strain.
Assuntos
Deleção de Genes , Ferro , Estresse Oxidativo , Proteínas Associadas a Pancreatite , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Ferro/metabolismo , Proteínas Associadas a Pancreatite/metabolismo , Proteínas Associadas a Pancreatite/genética , Regulação Fúngica da Expressão Gênica , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Espécies Reativas de Oxigênio/metabolismo , Viabilidade Microbiana , Fator de Ligação a CCAAT , Fatores de Transcrição de Zíper de Leucina BásicaRESUMO
Since the brain is the human body's primary command and control center, brain cancer is one of the most dangerous cancers. Automatic segmentation of brain tumors from multi-modal images is important in diagnosis and treatment. Due to the difficulties in obtaining multi-modal paired images in clinical practice, recent studies segment brain tumors solely relying on unpaired images and discarding the available paired images. Although these models solve the dependence on paired images, they cannot fully exploit the complementary information from different modalities, resulting in low unimodal segmentation accuracy. Hence, this work studies the unimodal segmentation with privileged semi-paired images, i.e., limited paired images are introduced to the training phase. Specifically, we present a novel two-step (intra-modality and inter-modality) curriculum disentanglement learning framework. The modality-specific style codes describe the attenuation of tissue features and image contrast, and modality-invariant content codes contain anatomical and functional information extracted from the input images. Besides, we address the problem of unthorough decoupling by introducing constraints on the style and content spaces. Experiments on the BraTS2020 dataset highlight that our model outperforms the competing models on unimodal segmentation, achieving average dice scores of 82.91%, 72.62%, and 54.80% for WT (the whole tumor), TC (the tumor core), and ET (the enhancing tumor), respectively. Finally, we further evaluate our model's variable multi-modal brain tumor segmentation performance by introducing a fusion block (TFusion). The experimental results reveal that our model achieves the best WT segmentation performance for all 15 possible modality combinations with 87.31% average accuracy. In summary, we propose a curriculum disentanglement learning framework for unimodal segmentation with privileged semi-paired images. Moreover, the benefits of the improved unimodal segmentation extend to variable multi-modal segmentation, demonstrating that improving the unimodal segmentation performance is significant for brain tumor segmentation with missing modalities. Our code is available at https://github.com/scut-cszcl/SpBTS.
Assuntos
Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo , Currículo , Processamento de Imagem Assistida por Computador/métodosRESUMO
The fission yeast Schizosaccharomyces pombe has two tRNase ZL genes (trz1 and trz2) involved in nuclear and mitochondrial tRNA 3'-end processing, respectively. Overexpression of trz2 but not trz1 is toxic to cells. In the present work, we showed that trz2 overexpression led to apoptotic cell death, as revealed by DAPI and Annexin V-FITC staining. Overexpression of trz2 also caused a loss of mitochondrial membrane potential and an increased reactive oxygen species (ROS) formation. These effects required mitochondrial localization but not its catalytic activity. RNA sequencing (RNA-seq) analysis revealed increased expression levels of genes involved in iron uptake and/or iron homeostasis, suggesting an elevated level of intracellular iron in the trz2-overexpressing cells. Indeed, we showed that overexpressing trz2 increased the level of intracellular iron by â¼2-fold. We further showed that the iron chelator, bathophenanthroline disulfonic acid (BPS) nearly restored the viability of trz2-overexpression cells and reduced ROS levels in the cells. These results suggest that trz2 overexpression may cause mitochondrial dysfunction, which is likely to lead to perturbation of iron homeostasis, ROS accumulation and induction of apoptotic cell death in S. pombe.