A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

Echtay, Karim S.; Esteves, Telma C.; Pakay, Julian L.; Jekabsons, Mika B.; Lambert, Adrian J.; Portero‐Otín, Manuel; Pamplona, Reinald; Vidal-Puig, António; Wang, Steven; Roebuck, Stephen J.; Brand, Martin D.

doi:10.1093/emboj/cdg412

Cited by 534 publications

(495 citation statements)

References 41 publications

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“…UCP3 is a mitochondrial inner membrane protein with unresolved physiological function(s). However, it has been hypothesised to mediate a proton leak when activated by HNE, reducing mitochondrial membrane potential and mitigating production of ROS in a negative feedback loop [39]. Interestingly, there were no differences in UCP3 expression between nondiabetic and post-diabetes mellitus participants under LGI conditions, but post-diabetes mellitus cells had lower expression of UCP3 at both the cellular and mitochondrial levels when exposed to HGI.…”

Section: Discussionmentioning

confidence: 96%

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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: Discussionmentioning

confidence: 96%

“…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: 92%

Increased susceptibility to oxidative damage in post-diabetic human myotubes

et al. 2009

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“…In fact, Echtay et al [28] also demonstrated that the uncoupling action of ANT as well as UCP was stimulated by 4-hydroxynonenal (HNE). It was also shown that knocking out one of two ANT isoenzymes (muscle-specific ANT1) results in a strong increase in ROS production by muscle mitochondria [29].…”

Section: Discussionmentioning

confidence: 99%

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat‐stressed chickens

et al. 2007

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We have shown that heat-stressed birds exhibit increased superoxide production in skeletal muscle mitochondria.To determine the precise mechanism for this effect, here we studied not only progressive, but also sequential changes in superoxide production, anion carriers and substrate oxidation in mitochondria of heat-stressed chickens. Exposure to acute heat stress (34°C for 6, 12 and 18 h) stimulated pectoralis muscle mitochondrial superoxide production. Heat stress-induced downregulations of avUCP gene transcripts and mitochondrial avUCP protein content were time-dependent: avUCP gene transcript was decreased after 6 h, while avUCP protein content was only downregulated after 12 h of heat stress. Avian adenine nucleotide translocator (avANT) gene transcripts were not changed on exposure to heat stress, suggesting that avANT may not be involved in the regulation of superoxide production in the muscle mitochondria of heat-stressed chickens. During the initial stage of acute heat stress b-oxidation enzymes gene transcripts and activity were upregulated, with elevated plasma non-esterified fatty acid levels and increased expression of mitochondrial fatty acid transport genes. This sudden surge in mitochondrial substrate oxidation resulted in higher superoxide production: the avUCP expression at 6 h after heat stress might have not been large enough to alleviate the overproduction of reactive oxygen species (ROS) even though a small amount of endogenous FFA, a potential uncoupler, might have been present in the mitochondria. Thereafter, avUCP content was downregulated while substrate oxidation returned to control levels. This downregulation of avUCP may have caused increased mitochondrial superoxide production, keeping the superoxide production high in the later stages of heat stress. These results suggest that overproduction of mitochondrial ROS in chicken skeletal muscle under the heat stress might result from enhanced substrate oxidation and downregulation of avUCP in a time-dependent manner.

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“…Modification of specific transcription factors, protein phosphatases or uncoupling proteins may affect the apoptotic threshold, the point of no return (such as the Bak-Bax gateway 12 ) or other RONS-mediated signaling effects on apoptosis 43 .…”

Section: Mitochondrial Rons Influence Cell Deathmentioning

confidence: 99%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

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We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

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A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

Cited by 534 publications

References 41 publications

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat‐stressed chickens

Lifespan and mitochondrial control of neurodegeneration

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