HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis

Zhou, Cheng; Li, Jue; Xinya, Jiang; Xu, Xuejun; Liu, Yi; He, Qun; Liang, Hui; Peng, Fang; Zhan, Huien; Zeng, Hui

doi:10.1016/j.biopha.2021.111378

Cited by 19 publications

(10 citation statements)

References 22 publications

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“…Interestingly, one of the up-regulated genes upon chchd4a −/− mutation is hmgcs1 encoding a key enzyme in the mevalonate pathway. Recently, HMGCS1 , its human orthologue, has been shown to activate unfolded protein response components (ATF4, XBP1, and ATF6) and protect mitochondria and ER from the damage under proteostatic stress ( Zhou et al, 2021 ). Increased cholesterol biosynthesis can also act as a compensatory mechanism reducing redox stress by consuming elevated NAD(P)H levels in the cell ( Schirris et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish

et al. 2022

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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 thechchd4a−/−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.

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Section: Resultsmentioning

confidence: 99%

Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish

et al. 2022

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“…HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) is also involved in the mevalonate pathway. It is a regulatory node in cholesterol biosynthesis, and may promote cell proliferation [ 41 ]. FADS2 (fatty acid desaturase 2) may be involved in the coordination of inflammatory responses and metabolic homeostasis [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Effects and associated transcriptomic landscape changes of methamphetamine on immune cells

Kong

Mao

et al. 2022

BMC Med Genomics

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Background Methamphetamine (METH) abuse causes serious health problems, including injury to the immune system, leading to increased incidence of infections and even making withdrawal more difficult. Of course, immune cells, an important part of the immune system, are also injured in methamphetamine abuse. However, due to different research models and the lack of bioinformatics, the mechanism of METH injury to immune cells has not been clarified. Methods We examined the response of three common immune cell lines, namely Jurkat, NK-92 and THP-1 cell lines, to methamphetamine by cell viability and apoptosis assay in vitro, and examined their response patterns at the mRNA level by RNA-sequencing. Differential expression analysis of two conditions (control and METH treatment) in three types of immune cells was performed using the DESeq2 R package (1.20.0). And some of the differentially expressed genes were verified by qPCR. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of differentially expressed genes by the clusterProfiler R package (3.14.3). And gene enrichment analysis was also performed using MetaScape (www.metascape.org). Results The viability of the three immune cells was differentially affected by methamphetamine, and the rate of NK-cell apoptosis was significantly increased. At the mRNA level, we found disorders of cholesterol metabolism in Jurkat cells, activation of ERK1 and ERK2 cascade in NK-92 cells, and disruption of calcium transport channels in THP-1 cells. In addition, all three cells showed changes in the phospholipid metabolic process. Conclusions The results suggest that both innate and adaptive immune cells are affected by METH abuse, and there may be commonalities between different immune cells at the transcriptome level. These results provide new insights into the potential effects by which METH injures the immune cells.

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“…A number of the DEGs detected in the presented research were downregulated in response to genotoxic stress in HCAEC. Hydroxy-3-methylglutaryl-CoA synthase 1 ( HMGCS1 ) is the gene encoding a key enzyme in the mevalonate pathway of cholesterol synthesis [ 86 ]. In addition, HMGCS1 can promote cell proliferation [ 87 ], enhance the integrated stress response (ISR) and interact with the endoplasmic reticulum stress transduction protein kinase [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

et al. 2022

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Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial disfunction underlying the atherogenesis can be triggered by genotoxic stress in endothelial cells. In the presented research whole transcriptome sequencing (RNA-seq) of human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells in vitro exposed to 500 ng/mL mitomycin C (treatment group) or 0.9% NaCl (control group) was performed. Resulting to bioinformatic analysis, 56 upregulated differentially expressed genes (DEGs) and 6 downregulated DEGs with absolute fold change ≥ 2 and FDR p-value < 0.05 were selected in HCAEC exposed to mitomycin C compared to the control group; in HITAEC only one upregulated DEG was found. According to Gene Ontology enrichment analysis, DEGs in HCAEC were classified into 25 functional groups of biological processes, while in HITAEC we found no statistically significant (FDR p-value < 0.05) groups. The four largest groups containing more than 50% DEGs (“signal transduction”, “response to stimulus”, “biological regulation”, and “regulation of biological process”) were identified. Finally, candidate DEGs and pathways underlying the genotoxic stress induced endothelial disfunction have been discovered that could improve our understanding of fundamental basis of atherogenesis and help to justification of genotoxic stress as a novel risk factor for atherosclerosis.

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HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis

Cited by 19 publications

References 22 publications

Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish

Profiling subcellular localization of nuclear-encoded mitochondrial gene products in zebrafish

Effects and associated transcriptomic landscape changes of methamphetamine on immune cells

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

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