Summary• Long chain bases (LCBs) are sphingolipid intermediates acting as second messengers in programmed cell death (PCD) in plants. Most of the molecular and cellular features of this signaling function remain unknown.• We induced PCD conditions in Arabidopsis thaliana seedlings and analyzed LCB accumulation kinetics, cell ultrastructure and phenotypes in serine palmitoyltransferase (spt), mitogen-activated protein kinase (mpk), mitogenactivated protein phosphatase (mkp1) and lcb-hydroxylase (sbh) mutants.• The lcb2a-1 mutant was unable to mount an effective PCD in response to fumonisin B1 (FB1), revealing that the LCB2a gene is essential for the induction of PCD. The accumulation kinetics of LCBs in wild-type (WT) and lcb2a-1 plants and reconstitution experiments with sphinganine indicated that this LCB was primarily responsible for PCD elicitation. The resistance of the null mpk6 mutant to manifest PCD on FB1 and sphinganine addition and the failure to show resistance on pathogen infection and MPK6 activation by FB1 and LCBs indicated that MPK6 mediates PCD downstream of LCBs.• This work describes MPK6 as a novel transducer in the pathway leading to LCBinduced PCD in Arabidopsis, and reveals that sphinganine and the LCB2a gene are required in a PCD process that operates as one of the more effective strategies used as defense against pathogens in plants.
Mitochondrion is an important metabolic and energetic organelle that regulates several cellular processes. Mitochondrial dysfunction has been related to liver diseases including hepatocellular carcinoma. As a result, the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. We previously demonstrated the chemopreventive effect of the hepatoprotector IFC-305. In this work we aimed to evaluate the functional, metabolic, and dynamic mitochondrial alterations in the sequential model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats and the possible beneficial effect of IFC-305. Experimental groups of rats were formed to induce cirrhosis-hepatocellular carcinoma and to assess the IFC-305 effect during cancer development and progression through the evaluation of functional, metabolic, and dynamic mitochondrial parameters. In this experimental model, dysfunctional mitochondria were observed and suspension of the diethylnitrosamine treatment was not enough to restore them. Administration of IFC-305 maintained and restored the mitochondrial function and regulated parameters implicated in metabolism as well as the mitochondrial dynamics modified by diethylnitrosamine intoxication. This study supports IFC-305 as a potential hepatocellular carcinoma treatment or as an adjuvant in chemotherapy.
S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl 4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemopreventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.
Hepatocellular carcinoma (HCC) is a pathology preceded mainly by cirrhosis of diverse etiology and is associated with uncontrolled dedifferentiation and cell proliferation processes. Many cellular functions are dependent on mitochondrial function, among which we can mention the enzymatic activity of PARP-1 and sirtuin 1, epigenetic regulation of gene expression, apoptosis, and so on. Mitochondrial dysfunction is related to liver diseases including cirrhosis and HCC; the energetic demand is not properly supplied and mitochondrial morphologic changes have been observed, resulting in an altered metabolism. There is a strong relationship between epigenetics and mitochondrion since the first one is dependent on the correct function of the last one. There is an interest to improve or to maintain mitochondrial integrity in order to prevent or reverse HCC; such is the case of IFC-305 that has a beneficial effect on mitochondrial function in a sequential model of cirrhosis-HCC. In this model, IFC-305 downregulates the expression of PCNA, thymidylate synthase, HGF and its receptor c-Met and upregulates the cell cycle inhibitor p27, thereby decreasing cell proliferation. Both effects, improvement of mitochondria function and reduction of tumor proliferation, suggest its use as HCC chemoprevention or as an adjuvant in chemotherapy.
Mitochondria are the center of energy production in eukaryotic cells and are crucial for several cellular processes. Dysfunctional mitochondria have been associated with cancer progression. Mitochondria contain their own circular DNA (mtDNA), which codes for 13 proteins, 2rRNA, 22tRNA and non-coding RNAs. Recent evidence showed the presence of 5-methylcytosine and 5-hydroximethylcytosine in mtDNA suggesting that the level of gene expression could be modulated like a nuclear DNA by direct epigenetic modifications. Mitoepigenetics is a bidirectional phenomenon in the epigenetic regulation of mitochondrial genes encoded in both the nucleus and the mitochondrion. This process is affected by SAM-mediated methylation and hydroxymethylation of mtDNA and by nuclear chromatin modulators from mitochondria, such as Acetyl-CoA and NAD +. There is some information about physiological and pathological methylated profiles, but information is scarce for hepatocellular carcinoma (HCC). The aim of this review is to summarize the mitoepigenetic knowledge in HCC already reported so far, through a keywords search in Medline. In addition, the deregulation of energy intermediaries needed for the mitoepigenetic regulation is described. As this is a new area of study, a rigorous analysis and careful interpretation and integration of results are needed.
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