Linking hypoxic and oxidative insults to cell death mechanisms in models of ALS

Xu, Renshi; Wu, Chengsi; Zhang, Xiong; Zhang, Qiong; Yang, Yongtao; Yi, Juan; Yang, Rong; Tao, Yuhui

doi:10.1016/j.brainres.2010.11.056

Cited by 30 publications

(20 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One reason of the higher ATP level in UCP4-overexpressing cells is possibly due to lower ATP consumption because the demand to cope with stress responses is presumably lower in UCP4-overexpressing cells. This postulation is reasonable because there is growing evidence to show that UCP4 has a regulatory role in the control of oxidative stress and ATP-consuming apoptotic processes [10], [24], [36]. This overall effect of higher ATP production in mitochondria and lower consumption in other regions of the cell helps to explain why overexpressing UCP4 is protective against ATP deficiency induced by the mitochondrial toxin, MPP + , as previously reported [10].…”

Section: Discussionsupporting

confidence: 58%

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Tse

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

Mitochondrial uncoupling protein-4 (UCP4) protects against Complex I deficiency as induced by 1-methyl-4-phenylpyridinium (MPP+), but how UCP4 affects mitochondrial function is unclear. Here we investigated how UCP4 affects mitochondrial bioenergetics in SH-SY5Y cells. Cells stably overexpressing UCP4 exhibited higher oxygen consumption (10.1%, p<0.01), with 20% greater proton leak than vector controls (p<0.01). Increased ATP supply was observed in UCP4-overexpressing cells compared to controls (p<0.05). Although state 4 and state 3 respiration rates of UCP4-overexpressing and control cells were similar, Complex II activity in UCP4-overexpressing cells was 30% higher (p<0.05), associated with protein binding between UCP4 and Complex II, but not that of either Complex I or IV. Mitochondrial ADP consumption by succinate-induced respiration was 26% higher in UCP4-overexpressing cells, with 20% higher ADP:O ratio (p<0.05). ADP/ATP exchange rate was not altered by UCP4 overexpression, as shown by unchanged mitochondrial ADP uptake activity. UCP4 overexpression retained normal mitochondrial morphology in situ, with similar mitochondrial membrane potential compared to controls. Our findings elucidate how UCP4 overexpression increases ATP synthesis by specifically interacting with Complex II. This highlights a unique role of UCP4 as a potential regulatory target to modulate mitochondrial Complex II and ATP output in preserving existing neurons against energy crisis.

show abstract

Section: Discussionsupporting

confidence: 58%

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Tse

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…These combined characteristics, along with alterations in protein folding and degradation (125), are interpreted to lead to excessive oxidative stress and cell death via impairment of autophagy and commitment to apoptosis. Although potential mediators of cell death have been identified in models of ALS (194), specific mechanisms of cell death have not been fully delineated. However, a role for reversible S-glutathionylation in ALS is implicated by model studies in which overexpression of Grx1 was found to increase the solubility of mutant SOD1 in the cytosol and overexpression of Grx2 increased its solubility in mitochondria and protected neuronal cells from apoptosis (54).…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

Liedhegner

Gao

Mieyal

2012

Antioxidants & Redox Signaling

107

View full text Add to dashboard Cite

Significance: Neurodegenerative diseases are characterized by progressive loss of neurons. A common feature is oxidative stress, which arises when reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) exceed amounts required for normal redox signaling. An imbalance in ROS/RNS alters functionality of cysteines and perturbs thiol-disulfide homeostasis. Many cysteine modifications may occur, but reversible protein mixed disulfides with glutathione (GSH) likely represents the common steady-state derivative due to cellular abundance of GSH and ready conversion of cysteine-sulfenic acid and S-nitrosocysteine precursors to S-glutathionylcysteine disulfides. Thus, S-glutathionylation acts in redox signal transduction and serves as a protective mechanism against irreversible cysteine oxidation. Reversal of protein-S-glutathionylation is catalyzed specifically by glutaredoxin which thereby plays a critical role in cellular regulation. This review highlights the role of oxidative modification of proteins, notably S-glutathionylation, and alterations in thiol homeostatic enzyme activities in neurodegenerative diseases, providing insights for therapeutic intervention. Recent Advances: Recent studies show that dysregulation of redox signaling and sulfhydryl homeostasis likely contributes to onset/progression of neurodegeneration. Oxidative stress alters the thiol-disulfide status of key proteins that regulate the balance between cell survival and cell death. Critical Issues: Much of the current information about redox modification of key enzymes and signaling intermediates has been gleaned from studies focused on oxidative stress situations other than the neurodegenerative diseases. Future Directions: The findings in other contexts are expected to apply to understanding neurodegenerative mechanisms. Identification of selectively glutathionylated proteins in a quantitative fashion will provide new insights about neuropathological consequences of this oxidative protein modification. Antioxid. Redox Signal. 16, 543-566.

show abstract

“…Superoxides generated during respiration can induce lipid peroxidation, which in turn activates UCPs to increase proton leak to diminish superoxide production in a negative feedback loop [44]. Neuronal UCP expression appears to be responsive to oxidative stress in various in vitro and in vivo experimental models of PD [32-34]. UCP2 and UCP5 expression were up-regulated in brains of patients after developing ischemic lesions from embolic stroke and multiple infarction [33].…”

Section: Reviewmentioning

confidence: 99%

Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

Liu

et al. 2012

Transl Neurodegener

View full text Add to dashboard Cite

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson's disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP+; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-κB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP+-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.

show abstract

Linking hypoxic and oxidative insults to cell death mechanisms in models of ALS

Cited by 30 publications

References 48 publications

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Uncoupling Protein-4 (UCP4) Increases ATP Supply by Interacting with Mitochondrial Complex II in Neuroblastoma Cells

Mechanisms of Altered Redox Regulation in Neurodegenerative Diseases—Focus on S-Glutathionylation

Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

Contact Info

Product

Resources

About