Protein targets for carbonylation by 4-hydroxy-2-nonenal in rat liver mitochondria

Guo, Jia; Prókai-Tátrai, Katalin; Nguyen, Vien; Rauniyar, Navin; Ughy, Bettina; Prókai, László

doi:10.1016/j.jprot.2011.07.009

Cited by 35 publications

(26 citation statements)

References 56 publications

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“…The metabolomic data are consistent with HNE-dependent inhibition of malate and isocitrate dehydrogenases, which would decrease metabolic flux through the TCA cycle (Supplementary Table 5). Additionally, there is evidence for the inhibition of the enzymatic activities of ATP synthase in rat liver mitochondria and isocitrate dehydrogenase in rat heart mitochondria by 4-HNE modifications [59, 60]. …”

Section: Discussionmentioning

confidence: 99%

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism

Ravi¹,

Johnson²,

Chacko³

et al. 2016

Free Radical Biology and Medicine

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Platelet aggregation is an essential response to tissue injury and is associated with activation of pro-oxidant enzymes, such as cyclooxygenase, and is also a highly energetic process. The two central energetic pathways in the cell, glycolysis and mitochondrial oxidative phosphorylation, are susceptible to damage by reactive lipid species. Interestingly, how platelet metabolism is affected by the oxidative stress associated with aggregation is largely unexplored. To address this issue, we examined the response of human platelets to 4-hydroxynonenal (4-HNE), a reactive lipid species which is generated during thrombus formation and during oxidative stress. Elevated plasma 4-HNE has been associated with renal failure, septic shock and cardiopulmonary bypass surgery. In this study, we found that 4-HNE decreased thrombin stimulated platelet aggregation by approximately 60%. The metabolomics analysis demonstrated that underlying our previous observation of a stimulation of platelet energetics by thrombin glycolysis and TCA (Tricarboxylic acid) metabolites were increased. Next, we assessed the effect of both 4-HNE and alkyne HNE (A-HNE) on bioenergetics and targeted metabolomics, and found a stimulatory effect on glycolysis, associated with inhibition of bioenergetic parameters. In the presence of HNE and thrombin glycolysis was further stimulated but the levels of the TCA metabolites were markedly suppressed. Identification of proteins modified by A-HNE followed by click chemistry and mass spectrometry revealed essential targets in platelet activation including proteins involved in metabolism, adhesion, cytoskeletal reorganization, aggregation, vesicular transport, protein folding, antioxidant proteins, and small GTPases. In summary, the biological effects of 4-HNE can be more effectively explained in platelets by the integrated effects of the modification of an electrophile responsive proteome rather than the isolated effects of candidate proteins.

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Section: Discussionmentioning

confidence: 99%

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism

Ravi¹,

Johnson²,

Chacko³

et al. 2016

Free Radical Biology and Medicine

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“…It has been reported that treatment of isolated crude animal mitochondria by HNE induces mitochondrial respiration deficiency [41, 49–51]. HNE modification of SDHA [52], DLD [29], ATP5B [53] as well as NDUFS2 [54] has been identified in vitro or in vivo under oxidative conditions by different reseachers. However, the exact proteins modified by HNE in mitochondrial respiration after DOX or HNE treatment have not been reported.…”

Section: Discussionmentioning

confidence: 99%

Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment

Zhao

Miriyala

Liu

et al. 2014

Free Radical Biology and Medicine

101

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Doxorubicin (DOX), one of the most effective anticancer drugs, is known to generate progressive cardiac damage, which is due, in part, to DOX-induced reactive oxygen species (ROS). The elevated ROS often induce oxidative protein modifications that result in alteration of protein functions. This study demonstrates that the level of proteins adducted by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, is significantly increased in mouse heart mitochondria following DOX treatment. A redox proteomics method involving 2D electrophoresis followed by mass spectrometry and investigation of protein data bases identified several HNE-modified mitochondria proteins, which were verified by HNE-specific immunoprecipitation in cardiac mitochondria from the DOX-treated mice. The majority of the identified proteins are related to mitochondrial energy metabolism. These include proteins in the citric acid cycle (TCA) and electron transport chain (ETC). The enzymatic activities of the HNE-adducted proteins were significantly reduced in DOX-treated mice. Consistent with the decline in the function of the HNE adducted proteins, the respiratory function of cardiac mitochondria as determined by oxygen consumption rate (OCR) was also significantly reduced after DOX treatment. The treatment with Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnP, an SOD mimic, averted the doxorubicin-induced mitochondrial dysfunctions as well as the HNE protein adductions. Together, the results demonstrate that free radical-mediated alteration of energy metabolism is an important mechanism mediating DOX-induced cardiac injury suggesting that metabolic intervention may represent a novel approach to preventing cardiac injury after chemotherapy.

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“…As such, identification of specific modified proteins and a better understanding of how the modification affects protein function is a necessary step. To date, several large proteomics studies have aided our understanding of both the specificity and localization of protein carbonyls in tissue, such as adipose, liver, skeletal muscle, plasma, lung, and cardiac tissue (46,48,49,(57)(58)(59)(60)(61). Mass-spectrometry-based approaches have allowed for the identification of hundreds of direct targets of 4-HNE, 4-HHE, and acrolein carbonylation targets with cytosolic, mitochondrial, ER, and nuclear localization.…”

Section: Lipid Peroxidation and Apoptosismentioning

confidence: 99%

Oxidative stress and lipotoxicity

Hauck

Bernlohr

2016

Journal of Lipid Research

244

175

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Protein targets for carbonylation by 4-hydroxy-2-nonenal in rat liver mitochondria

Cited by 35 publications

References 56 publications

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism

Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment

Oxidative stress and lipotoxicity

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