Translational inhibitors as potential therapeutic tool of human neuroblastoma through mitochondrial gene expression

2017 ◽  
Vol 41 (S1) ◽  
pp. S464-S464
Author(s):  
S. Hina
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
Neuroendocrine Tumour ◽  
Mitochondrial Gene ◽  
Mitochondrial Protein ◽  
Genetic Material ◽  
Neuronal Cell ◽  
Mitochondrial Proteins ◽  
Mitochondrial Gene Expression ◽  
Human Neuroblastoma

Neuroblastoma is a solid neuroendocrine tumour and most common type of cancer of infancy. It is a complex heterogeneous disease and many factors such as molecular, cellular and genetic features are involved in its development. Mitochondria play a pivotal role in neuronal cell survival or death. Neurons are highly reliant on aerobic oxidative phosphorylation (OXPHOS) for their energy needs. Defective activities of mitochondrial complexes I, II, III and IV have been identified in many neurological and neurodegenerative diseases. Human mitochondria with its own genetic material meet the needs required for the assembly of subunits of the oxidative phosphorylation (OXPHOS) complexes. A number of translational inhibitors are known that could potentially effect translation of mitochondrial protein synthesis. Among these puromycin, homoharringtonine and cyclohexamide were selected for the present study. The effect of these translational inhibitors on mitochondrial gene expression for the treatment of neuroblastoma are not well established. Therefore, in this study, we have investigated the effects of these translational inhibitors on the expression of human mitochondrial gene expression in SH-SY5Y neuroblastoma cells.We observed a significant effect on the level of mitochondrial transcripts upon exposure to these translation inhibitors in SH-SY5Y cells, however, the effects on expression of mitochondrial proteins were minimal. This suggests that translational inhibitors might not directly affect the abundance of mitochondrial proteins. Translational inhibitors induce significant effect on mitochondrial gene expression that can be lead to the new-targeted therapy for treating neuroblastoma.

scholarly journals Inactivation of the mitochondrial protease Afg3l2 results in severely diminished respiratory chain activity and widespread defects in mitochondrial gene expression

2020 ◽  
Author(s):  
Gautam Pareek ◽  
Leo J. Pallanck
Keyword(s):  
Gene Expression ◽  
Respiratory Chain ◽  
Ribosome Biogenesis ◽  
Mitochondrial Gene ◽  
Mitochondrial Proteins ◽  
Null Alleles ◽  
Mitochondrial Gene Expression ◽  
Genetic Approach ◽  
Mitochondrial Ribosome ◽  
Partial Inactivation

AbstractThe m-AAA proteases plays a critical role in the proteostasis of the inner mitochondrial membrane proteins, and mutations in the genes encoding these proteases cause severe incurable neurological diseases. To further explore the biological role of the m-AAA proteases and the pathological consequences of their deficiency, we used a genetic approach in the fruit fly Drosophila melanogaster to inactivate the ATPase family gene 3-like 2 (AFG3L2) gene, which encodes a component of the m-AAA proteases. We found that null alleles of Drosophila AFG3L2 die early in development, but partial inactivation of AFG3L2 using RNAi extended viability to the late pupal and adult stages of development. Flies with partial inactivation of Afg3l2 exhibited marked behavioral defects, neurodegeneration, mitochondrial morphological alterations, and diminished respiratory chain (RC) activity. Further work revealed that reduced RC activity was a consequence of widespread defects in mitochondrial gene expression, including diminished mitochondrial transcription, translation and impaired mitochondrial ribosome biogenesis. These defects were accompanied by the compensatory activation of the mitochondrial unfolded protein response (mito-UPR) and accumulation of unfolded mitochondrial proteins, including proteins involved in transcription. Overexpression of the mito-UPR components partially rescued the Afg3l2-deficient phenotypes, indicating that sequestration of essential components of the mitochondrial gene expression into aggregates partly accounts for these defects. However, Afg3l2 also co-sediments with the mitochondrial ribosome biogenesis machinery, suggesting an additional novel role for Afg3l2 in ribosome biogenesis. Our work suggests that strategies designed to modify mitochondrial stress pathways and mitochondrial gene expression could be therapeutic in the diseases caused by mutations in AFG3L2.Author SummaryMitochondria produce virtually all of the cellular energy through the actions of the respiratory chain (RC) complexes. However, both the assembly of the RC complexes, and their biological functions come at a cost. Biogenesis of the RC complexes depends on the coordinated expression of nuclear and mitochondrially encoded subunits and an imbalance in this process can cause protein aggregation. Moreover, the RC complexes produce highly damaging reactive oxygen species as a side product of their activity. The Mitochondrial AAA+ family of proteases are believed to provide the first line of defense against these insults. The importance of this protease family is best exemplified by the severe neurodegenerative diseases that are caused by mutations in their respective genes. To better understand the biological roles of the AAA+ proteases, and the physiological consequences of their inactivation we used a genetic approach in Drosophila to study the Afg3l2 AAA+ protease. Unexpectedly, we found that Afg3l2 deficiency profoundly impaired mitochondrial gene expression, including transcription, translation and ribosome biogenesis. These phenotypes were accompanied by accumulation of insoluble mitochondrial proteins, and compensatory activation of mito-UPR and autophagy. Our work indicates Afg3l2 plays critical roles in degrading unfolded mitochondrial proteins and regulating mitochondrial gene expression.

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

scholarly journals Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle.

1986 ◽  
Vol 261 (1) ◽  
pp. 376-380 ◽  
Author(s):  
R S Williams ◽  
S Salmons ◽  
E A Newsholme ◽  
R E Kaufman ◽  
J Mellor
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Contractile Activity ◽  
Mitochondrial Gene ◽  
Mitochondrial Gene Expression

scholarly journals Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria

2019 ◽  
Vol 47 (14) ◽  
pp. 7502-7517 ◽  
Author(s):  
Anna V Kotrys ◽  
Dominik Cysewski ◽  
Sylwia D Czarnomska ◽  
Zbigniew Pietras ◽  
Lukasz S Borowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Mitochondrial Gene ◽  
Binding Activity ◽  
Stress Conditions ◽  
Mitochondrial Rna ◽  
Mitochondrial Gene Expression ◽  
Compensatory Mechanisms ◽  
Temporary Reduction ◽  
Mitochondrial Transcription

AbstractMaintenance of mitochondrial gene expression is crucial for cellular homeostasis. Stress conditions may lead to a temporary reduction of mitochondrial genome copy number, raising the risk of insufficient expression of mitochondrial encoded genes. Little is known how compensatory mechanisms operate to maintain proper mitochondrial transcripts levels upon disturbed transcription and which proteins are involved in them. Here we performed a quantitative proteomic screen to search for proteins that sustain expression of mtDNA under stress conditions. Analysis of stress-induced changes of the human mitochondrial proteome led to the identification of several proteins with poorly defined functions among which we focused on C6orf203, which we named MTRES1 (Mitochondrial Transcription Rescue Factor 1). We found that the level of MTRES1 is elevated in cells under stress and we show that this upregulation of MTRES1 prevents mitochondrial transcript loss under perturbed mitochondrial gene expression. This protective effect depends on the RNA binding activity of MTRES1. Functional analysis revealed that MTRES1 associates with mitochondrial RNA polymerase POLRMT and acts by increasing mitochondrial transcription, without changing the stability of mitochondrial RNAs. We propose that MTRES1 is an example of a protein that protects the cell from mitochondrial RNA loss during stress.

scholarly journals Mitogenome Analysis of Four Lamiinae Species (Coleoptera: Cerambycidae) and Gene Expression Responses by Monochamus alternatus When Infected with the Parasitic Nematode, Bursaphelenchus mucronatus

Insects ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 453
Author(s):  
Zi-Yi Zhang ◽  
Jia-Yin Guan ◽  
Yu-Rou Cao ◽  
Xin-Yi Dai ◽  
Kenneth B. Storey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phylogenetic Trees ◽  
Mitochondrial Gene ◽  
Mitochondrial Protein ◽  
Pine Wilt Disease ◽  
Bursaphelenchus Xylophilus ◽  
Monochamus Alternatus ◽  
Genome Database ◽  
Protein Coding ◽  
Nd5 Gene

We determined the mitochondrial gene sequence of Monochamus alternatus and three other mitogenomes of Lamiinae (Insect: Coleoptera: Cerambycidae) belonging to three genera (Aulaconotus, Apriona and Paraglenea) to enrich the mitochondrial genome database of Lamiinae and further explore the phylogenetic relationships within the subfamily. Phylogenetic trees of the Lamiinae were built using the Bayesian inference (BI) and maximum likelihood (ML) methods and the monophyly of Monochamus, Anoplophora, and Batocera genera was supported. Anoplophora chinensis, An. glabripennis and Aristobia reticulator were closely related, suggesting they may also be potential vectors for the transmission of the pine wood pathogenic nematode (Bursaphelenchus xylophilus) in addition to M. alternatus, a well-known vector of pine wilt disease. There is a special symbiotic relationship between M. alternatus and Bursaphelenchus xylophilus. As the native sympatric sibling species of B. xylophilus, B. mucronatus also has a specific relationship that is often overlooked. The analysis of mitochondrial gene expression aimed to explore the effect of B. mucronatus on the energy metabolism of the respiratory chain of M. alternatus adults. Using RT-qPCR, we determined and analyzed the expression of eight mitochondrial protein-coding genes (COI, COII, COIII, ND1, ND4, ND5, ATP6, and Cty b) between M. alternatus infected by B. mucronatus and M. alternatus without the nematode. Expression of all the eight mitochondrial genes were up-regulated, particularly the ND4 and ND5 gene, which were up-regulated by 4–5-fold (p < 0.01). Since longicorn beetles have immune responses to nematodes, we believe that their relationship should not be viewed as symbiotic, but classed as parasitic.

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