Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang, Hui‐Chin; Chen, Ta Liang; Chen, Ruei Ming

doi:10.1124/dmd.108.023325

Cited by 33 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further work is needed to analyze these distinct functions of ATP synthase in ketamine-treated embryos. In conclusion, the current findings are consistent with reported adverse effects of ketamine on the mitochondria and ATP production in human cells (Baker et al, 2016; Chang et al, 2009; Ito et al, 2015), dysfunctional cardiac function in infant non-human primates (Hotchkiss et al, 2007) and newborn human infants (Saarenmaa et al, 2001), additionally providing mechanistic data that show ALCAR as a protectant against these adverse effects.…”

Section: Discussionsupporting

confidence: 91%

“…Ketamine led to mitochondrial dysfunction in neurons derived from human induced pluripotent stem cell (Ito et al, 2015) and acute ketamine administration has been shown to impair mitochondrial function in rat brains (Venancio et al, 2015). Ketamine suppresses ATP biosynthesis in HepG2 cells (Chang et al, 2009). However, the molecular mechanism of how ketamine causes mitochondrial dysfunction and suppresses ATP production is not known.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Robinson

Dumas

Ali

et al. 2018

Neurotoxicology and Teratology

View full text Add to dashboard Cite

Ketamine, a phencyclidine derivative, is an antagonist of the Ca2+-permeable N-methyl-D-aspartate (NMDA)-type glutamate receptors. It is a pediatric anesthetic and has been implicated in developmental neurotoxicity. Ketamine has also been shown to deplete ATP in mammalian cells. Our previous studies showed that acetyl L-carnitine (ALCAR) prevented ketamine-induced cardiotoxicity and neurotoxicity in zebrafish embryos. Based on our finding that ALCAR’s protective effect was blunted by oligomycin A, an inhibitor of ATP synthase, we further investigated the effects of ketamine and ALCAR on ATP levels, mitochondria and ATP synthase in zebrafish embryos. The results demonstrated that ketamine reduced ATP levels in the embryos but not in the presence of ALCAR. Ketamine reduced total mitochondrial protein levels and mitochondrial potential, which were prevented with ALCAR co-treatment. To determine the cause of ketamine-induced ATP deficiency, we explored the status of ATP synthase. The results showed that a subunit of ATP synthase, atp5α1, was transcriptionally down-regulated by ketamine, but not in the presence of ALCAR, although ketamine caused a significant upregulation in another ATP synthase subunit, atp5β and total ATP synthase protein levels. Most of the ATP generated by heart mitochondria are utilized for its contraction and relaxation. Ketamine-treated embryos showed abnormal heart structure, which was abolished with ALCAR co-treatment. This study offers evidence for a potential mechanism by which ketamine could cause ATP deficiency mediated by mitochondrial dysfunction.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Robinson

Dumas

Ali

et al. 2018

Neurotoxicology and Teratology

View full text Add to dashboard Cite

show abstract

“…Some studies have already investigated the relationship between F-actin and Ψ m in yeast and mammalian cells [56,57]. In yeast, a decrease in actin dynamics in certain actin mutants significantly reduced the mitochondrial membrane potential [58].…”

Section: Discussionmentioning

confidence: 99%

Disruption of actin filaments induces mitochondrial Ca2+ release to the cytoplasm and [Ca2+]c changes in Arabidopsis root hairs

Wang

Zhu

et al. 2010

BMC Plant Biol

View full text Add to dashboard Cite

BackgroundMitochondria are dynamic organelles that move along actin filaments, and serve as calcium stores in plant cells. The positioning and dynamics of mitochondria depend on membrane-cytoskeleton interactions, but it is not clear whether microfilament cytoskeleton has a direct effect on mitochondrial function and Ca2+ storage. Therefore, we designed a series of experiments to clarify the effects of actin filaments on mitochondrial Ca2+ storage, cytoplasmic Ca2+ concentration ([Ca2+]c), and the interaction between mitochondrial Ca2+ and cytoplasmic Ca2+ in Arabidopsis root hairs.ResultsIn this study, we found that treatments with latrunculin B (Lat-B) and jasplakinolide (Jas), which depolymerize and polymerize actin filaments respectively, decreased membrane potential and Ca2+ stores in the mitochondria of Arabidopsis root hairs. Simultaneously, these treatments induced an instantaneous increase of cytoplasmic Ca2+, followed by a continuous decrease. All of these effects were inhibited by pretreatment with cyclosporin A (Cs A), a representative blocker of the mitochondrial permeability transition pore (mPTP). Moreover, we found there was a Ca2+ concentration gradient in mitochondria from the tip to the base of the root hair, and this gradient could be disrupted by actin-acting drugs.ConclusionsBased on these results, we concluded that the disruption of actin filaments caused by Lat-B or Jas promoted irreversible opening of the mPTP, resulting in mitochondrial Ca2+ release into the cytoplasm, and consequent changes in [Ca2+]c. We suggest that normal polymerization and depolymerization of actin filaments are essential for mitochondrial Ca2+ storage in root hairs.

show abstract

“…For imaging analyses of ZO-1 and occludin tight junctions, these 2 proteins were immunodetected using polyclonal antibodies against rabbit anti-ZO-1 and occludin (Zymed). A confocal laser scanning microscope (Model FV500, Olympus) was utilized to analyze the samples (28).…”

Section: Methodsmentioning

confidence: 99%

Resveratrol Protects against Oxidized LDL-Induced Breakage of the Blood-Brain Barrier by Lessening Disruption of Tight Junctions and Apoptotic Insults to Mouse Cerebrovascular Endothelial Cells ,

Lin

Chang

Chen

et al. 2010

The Journal of Nutrition

Self Cite

View full text Add to dashboard Cite

Cerebrovascular endothelial cells (CEC) comprise the blood-brain barrier (BBB). In a previous study, we showed that oxidized LDL (oxLDL) can induce apoptosis of mouse CEC. Resveratrol possesses chemopreventive potential. This study aimed to evaluate the effects of resveratrol on oxLDL-induced insults to mouse CEC and its possible mechanisms. Exposure of mouse CEC to 200 μmol/L oxLDL for 1 h did not cause cell death but significantly altered the permeability and transendothelial electrical resistance of the cell monolayer. However, resveratrol completely normalized such injury. As for the mechanisms, resveratrol completely protected oxLDL-induced disruption of F-actin and microtubule cytoskeletons as well as occludin and zona occludens-1 (ZO-1) tight junctions. The oxLDL-induced decreases in the mitochondrial membrane potential and intracellular ATP levels were normalized by resveratrol. Exposure of mouse CEC to 200 μmol/L oxLDL for 24 h elevated oxidative stress and simultaneously induced cell apoptosis. However, resveratrol partially protected against oxLDL-induced CEC apoptosis. The oxLDL-induced alterations in levels of Bcl-2, Bax, and cytochrome c were completely normalized by resveratrol. Consequently, resveratrol partially decreased oxLDL-induced activation of caspases-9 and -3. Therefore, in this study, we show that resveratrol can protect against oxLDL-induced damage of the BBB through protecting disruption of the tight junction structure and apoptotic insults to CEC.

show abstract

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Cited by 33 publications

References 40 publications

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos

Disruption of actin filaments induces mitochondrial Ca2+ release to the cytoplasm and [Ca2+]c changes in Arabidopsis root hairs

Resveratrol Protects against Oxidized LDL-Induced Breakage of the Blood-Brain Barrier by Lessening Disruption of Tight Junctions and Apoptotic Insults to Mouse Cerebrovascular Endothelial Cells ,

Contact Info

Product

Resources

About