Cardiolipin Synthase-1 mRNA Expression Does Not Correlate with Endogenous Cardiolipin Synthase Enzyme Activity In Vitro and In Vivo in Mammalian Lipopolysaccharide Models of Inflammation

Lü, Biao; Xu, Fred Y.; Taylor, William A.; Feingold, Kenneth R.; Hatch, Grant M.

doi:10.1007/s10753-010-9230-3

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…The protein turnover rate of mammalian CLS is slow (Lu et al . ). This might account for the modest 37% reduction in CL mass observed in hCMEC/D3 cells with knock down of CLS.…”

Section: Discussionmentioning

confidence: 97%

“…RNAi-mediated knockdown of CLS in both human and other mammalian cells was previously reported to partially reduce CL levels (Choi et al 2007;Ji et al 2012;Chu et al 2013). The protein turnover rate of mammalian CLS is slow (Lu et al 2011). This might account for the modest 37% reduction in CL mass observed in hCMEC/D3 cells with knock down of CLS.…”

Section: Discussionmentioning

confidence: 98%

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Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Nguyen

Mejia

Chang

et al. 2016

Journal of Neurochemistry

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Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. Cardiolipin is a mitochondrial phospholipid required for function of the electron transport chain and ATP generation. We examined the role of cardiolipin in maintaining mitochondrial function necessary to support barrier properties of brain microvessel endothelial cells. Knockdown of the terminal enzyme of cardiolipin synthesis, cardiolipin synthase, in hCMEC/D3 cells resulted in decreased cellular cardiolipin levels compared to controls. The reduction in cardiolipin resulted in decreased mitochondrial spare respiratory capacity, increased pyruvate kinase activity, and increased 2-deoxy-[(3) H]glucose uptake and glucose transporter-1 expression and localization to membranes in hCMEC/D3 cells compared to controls. The mechanism for the increase in glucose uptake was an increase in adenosine-5'-monophosphate kinase and protein kinase B activity and decreased glycogen synthase kinase 3 beta activity. Knockdown of cardiolipin synthase did not affect permeability of fluorescent dextran across confluent hCMEC/D3 monolayers grown on Transwell(®) inserts. In contrast, knockdown of cardiolipin synthase resulted in an increase in 2-deoxy-[(3) H]glucose transport across these monolayers compared to controls. The data indicate that in hCMEC/D3 cells, spare respiratory capacity is dependent on cardiolipin. In addition, reduction in cardiolipin in these cells alters their cellular energy status and this results in increased glucose transport into and across hCMEC/D3 monolayers. Microvessel endothelial cells form part of the blood-brain barrier, a restrictively permeable interface that allows transport of only specific compounds into the brain. In human adult brain endothelial cell hCMEC/D3 monolayers cultured on Transwell(®) plates, knockdown of cardiolipin synthase results in decrease in mitochondrial cardiolipin and decreased mitochondrial spare respiratory capacity. The reduced cardiolipin results in an increased activity of adenosine monophosphate kinase (pAMPK) and protein kinase B (pAKT) and decreased activity of glycogen synthase kinase 3 beta (pGSK3β) which results in elevated glucose transporter-1 (GLUT-1) expression and association with membranes. This in turn increases 2-dexoyglucose uptake from the apical medium into the cells with a resultant 2-deoxyglucose movement into the basolateral medium.

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“…The protein turnover rate of mammalian CLS is slow (Lu et al . ). This might account for the modest 37% reduction in CL mass observed in hCMEC/D3 cells with knock down of CLS.…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Nguyen

Mejia

Chang

et al. 2016

Journal of Neurochemistry

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“…There appears to be tight coordination between translation and transcription of CLS in yeast (Su and Dowhan, 2006). Further, thyroxine has been shown to increase hepatic enzyme activity (Hostetler, 1991) and lipopolysaccharide decreases CLS mRNA levels in the liver (Lu et al, 2011). CLS1 normally resides within the inner membrane of mitochondria (Chen et al, 2006), where it could potentially colocalize with a pool of PINK1 (Meissner et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

et al. 2014

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SUMMARY Acute lung injury (ALI) is linked to mitochondrial injury, resulting in impaired cellular oxygen utilization; however, it is unknown how these events are linked on the molecular level. Cardiolipin, a mitochondrial-specific lipid, is generated by cardiolipin synthase (CLS1). Here, we show that S. aureus activates a ubiquitin E3 ligase component, Fbxo15, that is sufficient to mediate proteasomal degradation of CLS1 in epithelia, resulting in decreased cardiolipin availability and disrupted mitochondrial function. CLS1 is destabilized by the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), which binds CLS1 to phosphorylate and regulates CLS1 disposal. Like Fbxo15, PINK1 interacts with and regulates levels of CLS1 through a mechanism dependent upon Thr219. S. aureus infection upregulates this Fbxo15-PINK1 pathway to impair mitochondrial integrity, and Pink1 knockout mice are less prone to S. aureus-induced ALI. Thus, ALI-associated disruption of cellular bioenergetics involves bioeffectors that utilize a phosphodegron to elicit ubiquitin-mediated disposal of a key mitochondrial enzyme.

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“…The observed decrease in CLS activity could be a compensatory mechanism to counteract the increased CL formed in liver of PCC rats. We previously showed that CLS mRNA expression does not correlate with endogenous CLS enzyme activity [33]. In Micrococcus lysodeikticus the end-product of CL synthesis, CL, was shown to inhibit CLS at several concentrations [34].…”

Section: Discussionmentioning

confidence: 99%

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

Peyta

Jarnouen

Pinault

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p<0.02) and cardiolipin synthase (CLS) activity decreased 44% (p<0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p<0.01) and 50% (p<0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p<0.05), mitochondrial oxygen consumption 33% (p<0.05), PGPS gene expression 44% (p<0.05) and MLCL AT-1 activity 20% (p<0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.

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Cardiolipin Synthase-1 mRNA Expression Does Not Correlate with Endogenous Cardiolipin Synthase Enzyme Activity In Vitro and In Vivo in Mammalian Lipopolysaccharide Models of Inflammation

Cited by 8 publications

References 29 publications

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

Reduction in cardiolipin decreases mitochondrial spare respiratory capacity and increases glucose transport into and across human brain cerebral microvascular endothelial cells

E3 Ligase Subunit Fbxo15 and PINK1 Kinase Regulate Cardiolipin Synthase 1 Stability and Mitochondrial Function in Pneumonia

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

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