Homocysteine-dependent Alterations in Mitochondrial Gene Expression, Function and Structure

Austin, Richard C.; Sood, Sudesh K.; Dorward, Ann M.; Singh, Gurmit; Shaughnessy, Stephen G.; Pamidi, Sushmita; Outinen, P. A.; Weitz, Jeffrey I.

doi:10.1074/jbc.273.46.30808

Cited by 67 publications

(34 citation statements)

References 34 publications

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“…This effect could also be attributed to oxidative damage, which is particularly important in the mitochondrial compartment. High concentrations of Hcy on human megakaryocytic cell line cells decrease mitochondrial gene expression in the presence of physiological concentrations of Cu 2ϩ (14). The down-regulation of mitochondrial RNAs may be a general mechanism by which cells of liver of CBS Ϫ/Ϫ mice protect themselves against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Robert

Chassé

Santiard-Baron

et al. 2003

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up-or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.

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Section: Discussionmentioning

confidence: 99%

Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Robert

Chassé

Santiard-Baron

et al. 2003

Journal of Biological Chemistry

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“…Wingrave et al (37) suggested that increase in calcium activated the calpain and mediates mitochondrial damage during spinal cord injury in rats. Austin et al (3) suggested that the mitochondrial abnormalities are associated with HHcy. They observed mitochondrial damage in Dami cells with Hcy treatment and suggested the importance of glutathione and heat shock proteins in mitochondrial protection (3).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial abnormalities have been identified in HHcy (3,33). It is not determined whether Hcy-induced mitochondrial damage parallels the calpain activation.…”

mentioning

confidence: 99%

Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC

Moshal¹,

Singh²,

Sen³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC. Am J Physiol Heart Circ Physiol 291: H2825-H2835, 2006. First published July 28, 2006 doi:10.1152/ajpheart.00377.2006 is associated with atherosclerosis, stroke, and dementia. Hcy causes extracellular matrix remodeling by the activation of matrix metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine proteases that are implicated in mitochondrial damage via oxidative burst. Mitochondrial abnormalities have been identified in HHcy. The mechanism of Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial pathway is largely unknown. We report a novel role of calpains in mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart microvascular endothelial cells. Our observations suggested that calpain regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the enhanced calpain activity was not mirrored by the decreased levels of its endogenous inhibitor calpastatin. We presented evidence that Hcy induces the translocation of active calpain from cytosol to mitochondria, leading to MMP-9 activation, in part, by causing intramitochondrial oxidative burst. Furthermore, studies with pharmacological inhibitors of calpain (calpeptin and calpain-1 inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal cascade. Taken together, these findings determine the novel role of mitochondrial translocation of calpain-1 in MMP-9 activation during HHcy, in part, by increasing mitochondrial oxidative tress. cysteine proteases; thioredoxin; Nicotinamide adenine dinucleotide phosphate-oxidase-4; mitochondrial redox signaling; cardiovascular remodeling; calcium; extracellular regulated kinase 1/2; mitogenactivating protein kinase; calpastatin; antiproteolytic therapy; microvascular endothelial cells; matrix metalloproteinase-9 A GROWING BODY OF LITERATURE indicates that elevated levels of homocysteine [hyperhomocysteinemia (HHcy)] are an independent risk factor for coronary, cerebrovascular, and peripheral atherosclerotic diseases (5, 11, 12). Matrix metalloproteinases (MMPs) are the members of Zn-containing endopeptidases that share structural domains but differ in the substrate specificity, cellular sources, and induciblity that are responsible for matrix turnover. It is well known that Hcy-induced vascular dysfunction is caused by extracellular matrix remodeling. Hcy induces extracellular matrix remodeling by MMP-9 activation, in part, by inducing the redox signaling and modulating the intracellular calcium homeostasis (13,14,19,20).Calpains are the family of calcium-dependent cysteine proteases that have previously been i...

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“…This indicated that the effect was highly specific for homocysteine. Homocysteine has been reported to cause cell lysis when copper ion (4 -5 M) was present in medium (16,19,25). Because significantly less copper ion (8 nM or less) was present in the medium of our experiments, it is unlikely that this oxidative signal was involved in our assay.…”

Section: Cell Death Induced By Homocysteine Is Specific and Is Not Mementioning

confidence: 99%

Homocysteine Induces Programmed Cell Death in Human Vascular Endothelial Cells through Activation of the Unfolded Protein Response

Zhang

Cai

Adachi

et al. 2001

Journal of Biological Chemistry

268

189

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Severe hyperhomocysteinemia is associated with endothelial cell injury that may contribute to an increased incidence of thromboembolic disease. In this study, homocysteine induced programmed cell death in human umbilical vein endothelial cells as measured by TdTmediated dUTP nick end labeling assay, DNA ladder formation, induction of caspase 3-like activity, and cleavage of procaspase 3. Homocysteine-induced cell death was specific to homocysteine, was not mediated by oxidative stress, and was mimicked by inducers of the unfolded protein response (UPR), a signal transduction pathway activated by the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum. Dominant negative forms of the endoplasmic reticulum-resident protein kinases IRE1␣ and -␤, which function as signal transducers of the UPR, prevented the activation of glucose-regulated protein 78/immunoglobulin chain-binding protein and C/EBP homologous protein/growth arrest and DNA damage-inducible protein 153 in response to homocysteine. Furthermore, overexpression of the point mutants of IRE1 with defective RNase more effectively suppressed the cell death than the kinase-defective mutant. These results indicate that homocysteine induces apoptosis in human umbilical vein endothelial cells by activation of the UPR and is signaled through IRE1. The studies implicate that the UPR may cause endothelial cell injury associated with severe hyperhomocysteinemia.

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Homocysteine-dependent Alterations in Mitochondrial Gene Expression, Function and Structure

Cited by 67 publications

References 34 publications

Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Altered Gene Expression in Liver from a Murine Model of Hyperhomocysteinemia

Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC

Homocysteine Induces Programmed Cell Death in Human Vascular Endothelial Cells through Activation of the Unfolded Protein Response

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