Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production

SummaryGlucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved cysteine compound N-acetylcysteine (NAC) reduce GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

Mitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mitochondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored. Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes.

Gene Expression in 1-Methylcyclopropene (1-MCP) Treated Tomatoes during Pre-Climacteric Ripening Suggests Shared Regulation of Methionine Biosynthesis, Ethylene Production and Respiration

The physiology of fruit ripening is defined as either ‘climacteric’ or ‘non-climacteric’. In climacteric fruit respiration during ripening increases until it reaches a peak, which is accompanied by an increase in autocatalytic ethylene production, whereas the respiration of non-climacteric fruit does not increase and they have no requirement for ethylene to complete their ripening. In an attempt to gain further insight into the involvement of autocatalytic ethylene production with the climacteric rise in respiration, tomato fruit were harvested at three defined stages of maturity prior to the climacteric peak (mature green, breaker, and early orange) and immediately exposed to the gaseous molecule 1-methylcyclopropene (1-MCP). The gene expression profile at each of these stages was monitored after 24 h, using an Affymetrix tomato microarray chip. This approach enabled us to identify ethylene responsive genes that are commonly regulated at early stages of ripening, as well as new candidate genes. In addition, 1-MCP treatment affected the levels of metabolites related to methionine biosynthesis. Methionine feeds climacteric ethylene production and we found that promotors of the genes of enzymes that catalyze the production of homoserine and homocysteine (aspartokinase/homoserine dehydrogenases and cystathionine beta lyase, respectively), precursors in the methionine pathway, contain the AtSR1 binding motif. This binding motif is recognized by ethylene activated transcription factors, hence indicating a role for ethylene in methionine synthesis during early ripening, explaining the autocatalytic ethylene production during subsequent ripening stages.

Impairment of MET transcriptional activators, MET4 and MET31 induced lipid accumulation in Saccharomyces cerevisiae

ABSTRACT The genes involved in the methionine pathway are closely associated with phospholipid homeostasis in yeast. The impact of the deletion of methionine (MET) transcriptional activators (MET31, MET32 and MET4) in lipid homeostasis is studied. Our lipid profiling data showed that aberrant phospholipid and neutral lipid accumulation occurred in met31∆ and met4∆ strains with low Met. The expression pattern of phospholipid biosynthetic genes such as CHO2, OPI3 and triacylglycerol (TAG) biosynthetic gene, DGA1 were upregulated in met31∆, and met4∆ strains when compared to wild type (WT). The accumulation of triacylglycerol and sterol esters (SE) content supports the concomitant increase in lipid droplets in met31∆ and met4∆ strains. However, excessive supplies of methionine (1 mM) in the cells lacking the MET transcriptional activators MET31 and MET4 ameliorates the abnormal lipogenesis and causes aberrant lipid accumulation. These findings implicate the methionine accessibility plays a pivotal role in lipid metabolism in the yeast model.

The role of folate receptor and reduced folate carrier polymorphisms in osteoporosis development

Summary Introduction: Osteoporosis is a chronic metabolic disease with multifactorial etiology. One of possible osteoporosis causes may be impairment of osteoclasts function which leads to increased bone resorption. This may be a result of many metabolic changes. It is believed that changes of folate-methionine metabolism in osteoporosis play an essential role in the etiology of this disease. Objective: The aim of this study was to examine how polymorphisms of SLC19A1 and FOLR3 genes may play the key role in folate-methionine pathway and influence on the etiology of osteoporosis. Results: The statistically overrepresentation of mutated GG genotype of FOLR3 (rs11235449) was observed in the control group compared to the osteopenia (34.9% in osteopenia vs. 37.8% in controls, p=0.025, OR=0.61). As to the SLC19A1 (rs3788200) polymorphism we have noted the statistically significant over-representation of wild-type GG genotype (35.8% vs. 26.2%, p=0.046, OR=1.57) and overrepresentation of wild-type G allele (56.9% vs. 50.2%, p=0.061, OR=1.31) in osteopenia group if compared to the controls. Conclusions: In our study we shown the protective role of mutated GG genotype of FOLR3 (rs11235449) polymorphism to osteopenia progress and possible role of wild-type GG genotype and wild-type G allele of SLC19A1 (rs3788200) polymorphism in osteopenia development.