Reduced expression of citrate synthase leads to excessive superoxide formation and cell apoptosis

Cai, Quanxiang; Zhao, Mengmeng; Liu, Xiang; Wang, Xiaochun; Nie, Yao; Li, Ping; Liu, Tingyan; Ge, Ruli; Han, Fengchan

doi:10.1016/j.bbrc.2017.02.067

Cited by 35 publications

(20 citation statements)

References 36 publications

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“…Contrary to parathion, CPF and dichlorvos induced a loss of neuronal cell CS activity which may reflect a loss of mitochondrial enrichment. A decrease in CS activity has previously been associated with a decrease in cellular ATP production, an increase in ROS production and accelerated cell death [50]. This may explain to some degree the evidence of cellular toxicity and loss of cell viability indicated by the MTT assay following exposure to OPs at concentrations of 50 µM and 100 µM.…”

Section: Discussionmentioning

confidence: 85%

The Effect of Organophosphate Exposure on Neuronal Cell Coenzyme Q10 Status

et al. 2020

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Organophosphate (OP) compounds are widely used as pesticides and herbicides and exposure to these compounds has been associated with both chronic and acute forms of neurological dysfunction including cognitive impairment, neurophysiological problems and cerebral ataxia with evidence of mitochondrial impairment being associated with this toxicity. In view of the potential mitochondrial impairment, the present study aimed to investigate the effect of exposure to commonly used OPs, dichlorvos, methyl-parathion (parathion) and chloropyrifos (CPF) on the cellular level of the mitochondrial electron transport chain (ETC) electron carrier, coenzyme Q 10 (CoQ 10) in human neuroblastoma SH-SY5Y cells. The effect of a perturbation in CoQ 10 status was also evaluated on mitochondrial function and cell viability. A significant decreased (P < 0.0001) in neuronal cell viability was observed following treatment with all three OPs (100 µM), with dichlorvos appearing to be the most toxic to cells and causing an 80% loss of viability. OP treatment also resulted in a significant diminution in cellular CoQ 10 status, with levels of this isoprenoid being decreased by 72% (P < 0.0001), 62% (P < 0.0005) and 43% (P < 0.005) of control levels following treatment with dichlorvos, parathion and CPF (50 µM), respectively. OP exposure was also found to affect the activities of the mitochondrial enzymes, citrate synthase (CS) and mitochondrial electron transport chain (ETC) complex II+III. Dichlorvos and CPF (50 µM) treatment significantly decreased CS activity by 38% (P < 0.0001) and 35% (P < 0.0005), respectively compared to control levels in addition to causing a 54% and 57% (P < 0.0001) reduction in complex II+III activity, respectively. Interestingly, although CoQ 10 supplementation (5 μM) was able to restore cellular CoQ 10 status and CS activity to control levels following OP treatment, complex II+III activity was only restored to control levels in neuronal cells exposed to dichlorvos (50 µM). However, post supplementation with CoQ 10 , complex II+III activity significantly increased by 33% (P < 0.0005), 25% (P < 0.005) and 35% (P < 0.0001) in dichlorvos, parathion and CPF (100 µM) treated cells respectively compared to non-CoQ 10 supplemented cells. In conclusion, the results of this study have indicated evidence of neuronal cell CoQ 10 deficiency with associated mitochondrial dysfunction following OP exposure. Although CoQ 10 supplementation was able to ameliorate OP induced deficiencies in CS activity, ETC complex II+III activity appeared partially refractory to this treatment. Accordingly, these results indicate the therapeutic potential of CoQ 10 supplementation in the treatment of OP poisoning. However, higher doses may be required to engender therapeutic efficacy.

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Section: Discussionmentioning

confidence: 85%

The Effect of Organophosphate Exposure on Neuronal Cell Coenzyme Q10 Status

et al. 2020

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“…We performed the same time course experiments and we observed that only Au(NHC) 2 led to a 2.5-fold increase of mitochondrial ROS production after 72 h of treatment (Figure 7C ). Since increase of mitochondrial ROS may be initiated by dysfunctional mitochondria [ 49 ], we analysed by flow-cytometry the mitochondrial membrane potential (Δψ m ), on the same treated-cells, using the cyanine dye DiIC1(5) (Figure 7D ). In line with the data on mitochondrial superoxide anion levels, this experiment pointed out that only Au(NHC) 2 affected the Δψ m and after 72 h of exposure.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study

et al. 2018

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Au(NHC) and Au(NHC)2, i.e. a monocarbene gold(I) complex and the corresponding bis(carbene) complex, are two structurally related compounds, endowed with cytotoxic properties against several cancer cell lines. Herein, we explore the molecular and cellular mechanisms at the basis of their cytotoxicity in A2780 human ovarian cancer cells. Through a comparative proteomic analysis, we demonstrated that the number of modulated proteins is far larger in Au(NHC)2-treated than in Au(NHC)-treated A2780 cells. Both gold compounds mainly affected proteins belonging to the following functional classes: protein synthesis, metabolism, cytoskeleton and stress response and chaperones. Particularly, Au(NHC)2 gave rise to an evident upregulation of several glycolytic enzymes. Moreover, only Au(NHC)2 triggered a net impairment of respiration and a metabolic shift towards glycolysis, suggesting that mitochondria are relevant cellular targets. We also found that both carbenes, similarly to the gold(I) compound auranofin, caused a strong inhibition of the seleno-enzyme thioredoxin reductase (TrxR). In conclusion, we highlighted that coordination of two carbene ligands to the same gold(I) center greatly enhances the antiproliferative effects of the resulting compound in comparison to the monocarbene derivative. Moreover, TrxR inhibition and metabolic impairment seem to play a major role in the Au(NHC)2 cytotoxicity. Overall, these antiproliferative effects were also confirmed on other two human ovarian cancer cell lines (i.e. SKOV3 and IGROV1).

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“…Citrate synthase is a key mitochondrial matrix enzyme and a strong indicator of oxidative capacity in skeletal muscle [ 56 , 57 , 58 , 59 ] and maximal citrate synthase activity was also found to strongly correlate with mitochondrial volume measured by electron microscopy in skeletal muscles of healthy, young men [ 58 ]. Porin (also known as voltage dependent anion channel, VDAC1) is a pore-forming protein localized in the outer membrane of mitochondria, and is used as a marker of mitochondrial content [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning

Fritzen

Thøgersen

Qadri

et al. 2020

JCM

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Aging is related to an inevitable loss of muscle mass and strength. The mechanisms behind age-related loss of muscle tissue are not fully understood but may, among other things, be induced by age-related differences in myogenic regulatory factors. Resistance exercise training and deconditioning offers a model to investigate differences in myogenic regulatory factors that may be important for age-related loss of muscle mass and strength. Nine elderly (82 ± 7 years old) and nine young, healthy persons (22 ± 2 years old) participated in the study. Exercise consisted of six weeks of resistance training of the quadriceps muscle followed by eight weeks of deconditioning. Muscle biopsy samples before and after training and during the deconditioning period were analyzed for MyoD, myogenin, insulin-like growth-factor I receptor, activin receptor IIB, smad2, porin, and citrate synthase. Muscle strength improved with resistance training by 78% (95.0 ± 22.0 kg) in the elderly to a similar extent as in the young participants (83.5%; 178.2 ± 44.2 kg) and returned to baseline in both groups after eight weeks of deconditioning. No difference was seen in expression of muscle regulatory factors between elderly and young in response to exercise training and deconditioning. In conclusion, the capacity to gain muscle strength with resistance exercise training in elderly was not impaired, highlighting this as a potent tool to combat age-related loss of muscle function, possibly due to preserved regulation of myogenic factors in elderly compared with young muscle.

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Reduced expression of citrate synthase leads to excessive superoxide formation and cell apoptosis

Cited by 35 publications

References 36 publications

The Effect of Organophosphate Exposure on Neuronal Cell Coenzyme Q10 Status

The Effect of Organophosphate Exposure on Neuronal Cell Coenzyme Q10 Status

Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study

Preserved Capacity for Adaptations in Strength and Muscle Regulatory Factors in Elderly in Response to Resistance Exercise Training and Deconditioning

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