Adenine Nucleotide Translocase Is Acetylated <i>in Vivo</i> in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

Mielke, Clinton; Lefort, Natalie; McLean, Carrie G.; Cordova, Jeanine M.; Langlais, Paul; Bordner, Andrew J.; Te, Jerez A.; Ozkan, S. Banu; Willis, Wayne T.; Mandarino, Lawrence J.

doi:10.1021/bi401651e

Cited by 49 publications

(48 citation statements)

References 43 publications

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“…This can lead to a vicious cycle between mitochondrial dysfunction and mitochondrial oxidative stress which can be mediated by hyperacetylation of mitochondrial proteins. Indeed, our LC-MS/MS analysis of hypertensive mice show significant increase in lysine acetylation of more than thirty enzymes critically involved in electron transport chain, redox processes and ATP synthesis such as ADP/ATP translocase 40 and ATP synthase (Supplemental Table II), and many of these proteins are hyperacetylated in a Sirt3 dependent manner (Supplemental Table III). In metabolic syndrome, hyperlipidemia, diabetes and sedentary lifestyle Sirt3 activity is metabolically downregulated by increased Acetyl-CoA and reduced NAD + .…”

Section: Discussionmentioning

confidence: 97%

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension

Dikalova

Itani

Nazarewicz

et al. 2017

Circulation Research

219

158

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Rationale Clinical studies have shown that Sirt3 expression declines by 40% by age 65 paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 due to increased NADH and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), due to hyperacetylation. Objective In this study we examined if loss of Sirt3 activity increases vascular oxidative stress due to SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension. Methods and Results Hypertension was markedly increased in Sirt3 knockout (Sirt3−/−) and SOD2 depleted (SOD2+/−) mice in response to low dose of angiotensin II (0.3 mg/kg/day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O2•, and diminished endothelial nitric oxide. Angiotensin II induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2 and reduced SOD2 activity. Scavenging of mitochondrial H2O2 in mCAT mice prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H2O2 scavenger, mitoEbselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation and reduced blood pressure in wild-type but not in Sirt3−/− mice while an SOD2 mimetic, mitoTEMPO, reduced blood pressure and improved vasorelaxation both in Sirt3−/− and wild type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels while SOD2 expression was not affected. Conclusions Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.

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Section: Discussionmentioning

confidence: 97%

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension

Dikalova

Itani

Nazarewicz

et al. 2017

Circulation Research

219

158

View full text Add to dashboard Cite

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“…We observed most marked hyperacetylation on ES1, IF1, TFEα, 3 lysine acetylation sites on the ADP‐ATP translocase 1, isocitrate dehydrogenase [NADP], acyl‐CoA thioesterase 8, mMDH2, and GDH1 in INS‐1E SIRT3KO cells. Lysine acetylation of TFEα (38), ADP‐ATP translocase 1 (39), isocitrate dehydrogenase [NADP] (36), MDH2 (1), and GDH1 (11, 13) has been observed previously in other cell types or tissues. Importantly, for several of these enzymes (1, 13, 36, 39), their activity is regulated by lysine acetylation (see also the earlier section of the Discussion).…”

Section: Discussionmentioning

confidence: 58%

Mitochondrial lysine deacetylation promotes energy metabolism and calcium signaling in insulin‐secreting cells

Marchi¹,

Galindo

Thévenet³

et al. 2018

FASEB j.

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In pancreatic β‐cells, mitochondria generate signals that promote insulin granule exocytosis. Here we study how lysine acetylation of mitochondrial proteins mechanistically affects metabolism‐secretion coupling in insulin‐secreting cells. Using mass spectrometry‐based proteomics, we identified lysine acetylation sites in rat insulinoma cell line clone 1E cells. In cells lacking the mitochondrial lysine deacetylase sirtuin‐3 (SIRT3), several matrix proteins are hyperacetylated. Disruption of the SIRT3 gene has a deleterious effect on mitochondrial energy metabolism and Ca2+ signaling. Under resting conditions, SIRT3 deficient cells are overactivated, which elevates the respiratory rate and enhances calcium signaling and basal insulin secretion. In response to glucose, the SIRT3 knockout cells are unable to mount a sustained cytosolic ATP response. Calcium signaling is strongly reduced and the respiratory response as well as insulin secretion are blunted. We propose mitochondrial protein lysine acetylation as a control mechanism in β‐cell energy metabolism and Ca2+ signaling.—De Marchi, U., Galindo, A. N., Thevenet, J., Hermant, A., Bermont, F., Lassueur, S., Domingo, J. S., Kussmann, M., Dayon, L., Wiederkehr, A. Mitochondrial lysine deacetylation promotes energy metabolism and calcium signaling in insulin‐secreting cells. FASEB J. 33, 4660–4674 (2019). http://www.fasebj.org

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“…Lysine acetylation regulates key exercise-responsive aspects of mitochondrial function in skeletal muscle (Philp et al 2014). Acetylation status correlates with human insulin sensitivity (Mielke et al 2014) and age-related adaptive responses to exercise training that help maintain quality and protect against oxidative damage of mitochondrial proteins (Johnson et al 2015). Together, these findings warrant further global acetylome investigations in human tissues.…”

Section: Phosphoproteome and Acetylomementioning

confidence: 95%

Omics and Exercise: Global Approaches for Mapping Exercise Biological Networks

Hoffman

2017

Cold Spring Harb Perspect Med

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The application of global "-omics" technologies to exercise has introduced new opportunities to map the complexity and interconnectedness of biological networks underlying the tissue-specific responses and systemic health benefits of exercise. This review will introduce major research tracks and recent advancements in this emerging field, as well as critical gaps in understanding the orchestration of molecular exercise dynamics that will benefit from unbiased omics investigations. Furthermore, significant research hurdles that need to be overcome to effectively fill these gaps related to data collection, computation, interpretation, and integration across omics applications will be discussed. Collectively, a cross-disciplinary physiological and omics-based systems approach will lead to discovery of a wealth of novel exercise-regulated targets for future mechanistic validation. This frontier in exercise biology will aid the development of personalized therapeutic strategies to improve athletic performance and human health through precision exercise medicine.T he dynamic human physiological responses to exercise have been widely studied in the context of metabolism and mechanical stress. Health benefits of exercise in prevention, delay, and/or treatment of pathophysiology associated with metabolic disorders and aging are widely appreciated. However, the intricacies of molecular networks and biological mechanisms underlying how humans adapt to exercise and acquire health benefits are not fully understood. In response to perturbations in whole-body homeostasis induced by physical activity and exercise, biological networks are stimulated in various cell types and organs to manage systemic metabolic and mechanical demands (Hawley et al. 2014). Targeted, reductionist-based approaches have laid the foundation for our understanding of distinct biological mechanisms regulating acute versus repeated exercise adaptations using a range of experimental models from cells to animals and humans. However, the complexity and integrated nature of the whole-body exercise response warrants global unbiased systems approaches to unravel the interwoven networks underlying the benefits of exercise in health and disease.In this early stage of the exercise and omics revolution, there is a wealth of molecular information now within reach to help build on our understanding of human metabolism and exercise physiology. There is tremendous potential for omics approaches to fill critical gaps in our

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Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

Cited by 49 publications

References 43 publications

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension

Mitochondrial lysine deacetylation promotes energy metabolism and calcium signaling in insulin‐secreting cells

Omics and Exercise: Global Approaches for Mapping Exercise Biological Networks

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