Superoxide activates mitochondrial uncoupling proteins

Echtay, Karim S.; Roussel, Damien; St‐Pierre, Julie; Jekabsons, Mika B.; Cadenas, Susana; Stuart, Jeffrey A.; Harper, J. A.; Roebuck, Stephen J.; Morrison, Alastair; Pickering, Susan J.; Clapham, John C.; Brand, Martin D.

doi:10.1038/415096a

Cited by 1,252 publications

(1,120 citation statements)

References 29 publications

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“…4). It has been hypothesised that UCP3 may mitigate ROS production by uncoupling oxidative phosphorylation in situations of high membrane potential [37][38][39]. No overall differences in UCP3 protein content were observed between post-diabetes mellitus and non-diabetic myotubes under LGI conditions (Fig.…”

Section: 000mentioning

confidence: 93%

Increased susceptibility to oxidative damage in post-diabetic human myotubes

et al. 2009

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Aims/hypothesis Obesity is an important risk factor for the development of type 2 diabetes, but not all obese individuals develop this complication. The clinical signs of type 2 diabetes can often be reversed with weight loss; however, it is unknown whether the skeletal muscle oxidative stress associated with type 2 diabetes remains after weight loss. We hypothesised that chronic exposure to high glucose and insulin would re-elicit impaired metabolism in primary myotubes from patients with a history of type 2 diabetes. Methods Obese participants with or without type 2 diabetes completed a standardised weight loss protocol, following which all participants were euglycaemic and had similar indices of insulin sensitivity. Satellite cells were isolated from muscle biopsies and differentiated under low or high glucose and insulin conditions (HGI).

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Section: 000mentioning

confidence: 93%

Increased susceptibility to oxidative damage in post-diabetic human myotubes

et al. 2009

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“…16 We measured mitochondrial production of superoxide (O 2 KÀ ) by using MitoSOX red-mitochondrial superoxide indicator. Complex II-deficient cells displayed an increase in mitochondrial O 2 KÀ production of almost 25% as compared with control ( Figure 1c; Supplementary Table S3).…”

Section: Resultsmentioning

confidence: 99%

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

et al. 2010

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Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca 2 þ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Dw mit ) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca 2 þ overload are linked to increased endoplasmic reticulum (ER) Ca 2 þ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca 2 þ ] mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca 2 þ ] activated on the one hand a compensatory Ca 2 þ -dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca 2 þ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. Mitochondria are the driving force behind life, as mitochondrial oxidative phosphorylation provides the main source of ATP in the cell. In addition to energy production, mitochondria have a crucial function in mediating amino-acid biosynthesis, fatty acid oxidation, intermediate metabolic pathways, free radicals production and Ca 2 þ homeostasis. 1 Mitochondria affect intracellular Ca 2 þ metabolism in two ways: (i) directly by regulating both the amplitude, duration, location and propagation of cytosolic Ca 2 þ elevations and the recycling of Ca 2 þ towards the endoplasmic reticulum (ER) and 2 (ii) indirectly by producing ATP, which is used by Ca 2 þ -dependent ATPases to pump Ca 2 þ out of the cell (by the plasma-membrane Ca 2 þ ATPase: PMCA) or into intracellular stores (by the sarco-ER Ca 2 þ ATPase: SERCA). Conversely, Ca 2 þ entering to the mitochondrial matrix regulates mitochondrial metabolism through the activation of the Ca 2 þ -dependent enzymes of the Krebs cycle. 3 Leigh's syndrome is a rare but severe and fatal encephalopathy of early childhood that is most frequently associated with deficiencies in nucleus-encoded subunits of Complex I (NDUFS3 and NDUFS7), 4,5 Complex II (SDHA), 6 Complex IV (SURF1) 7 or pyruvate dehydrogenase. 8 Despite the identification of the genetic origin of Leigh's syndrome, the molecular and cellular events associated with pathology are not completely understood.Deregulations of intracellular Ca 2 þ signalling have been reported in different models of mitochondrial respiratory chain diseases, 9-11 whereas data on Complex II deficiency are still lacking.Complex II (succinate: ubiquinone (UQ) oxidoreductase) has a central function in oxidative metabolism, being an importan...

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“…However, in a cellular system, UCP1 has no uncoupling activity, unless adequately stimulated. Recent studies in mitochondria obtained from tissues with different levels of UCP2 or UCP3 show that these proteins exhibit uncoupling activity only in the presence of ROS, in particular superoxide of mitochondrial origin, with or without fatty acids [21]. As mitochondrial ROS production is dependent on the mitochondrial potential, mild uncoupling could effectively decrease ROS generation.…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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Superoxide activates mitochondrial uncoupling proteins

Cited by 1,252 publications

References 29 publications

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

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