Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Lu, Zhongping; Chen, Yong; Aponte, Angel; Battaglia, Valentina; Guček, Marjan; Sack, Michael N.

doi:10.1074/jbc.m114.606228

Cited by 49 publications

(27 citation statements)

References 47 publications

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“…; Lu et al . ). Following fasting, altered SIRT3 expression may contribute to the regulation of fatty acid oxidation and oxidative metabolism in murine skeletal muscle (Shi et al .…”

Section: Introductionmentioning

confidence: 97%

SIRT3 gene expression but not SIRT3 subcellular localization is altered in response to fasting and exercise in human skeletal muscle

Edgett

Hughes

Matusiak

et al. 2016

Experimental Physiology

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What is the central question of this study? Evidence from cellular and animal models suggests that SIRT3 is involved in regulating aerobic ATP production. Thus, we investigated whether changes in fatty acid and oxidative metabolism known to accompany fasting and exercise occur in association with changes in SIRT3 mitochondrial localization and expression in human skeletal muscle. What is the main finding and its importance? We find that 48 h of fasting and acute endurance exercise decrease SIRT3 mRNA expression but do not alter SIRT3 mitochondrial localization despite marked increases in fatty acid oxidation. This suggests that SIRT3 activity is not regulated by changes in mitochondrial localization in response to cellular energy stress in human skeletal muscle. The present study examined SIRT3 expression and SIRT3 mitochondrial localization in response to acute exercise and short-term fasting in human skeletal muscle. Experiment 1 involved eight healthy men (age, 21.4 ± 2.8 years; peak O2 uptake, 47.1 ± 11.8 ml min(-1) kg(-1) ) who performed a single bout of exercise at ∼55% of peak aerobic work rate for 1 h. Muscle biopsies were obtained at rest (Rest), immediately after exercise (EX-0) and 3 h postexercise (EX-3). Experiment 2 involved 10 healthy men (age, 22.0 ± 1.5 years; peak O2 uptake, 46.9 ± 6.0 ml min−1 kg−1) who underwent a 48 h fast, with muscle biopsies collected 1 h postprandial (Fed) and after 48 h of fasting (Fast). Mitochondrial respiration was measured using high-resolution respirometry in permeabilized muscle fibre bundles to assess substrate oxidation. Whole body fat oxidation increased after both exercise (Rest, 0.96 ± 0.32 kcal min(-1) ; Exercise, 5.66 ± 1.97 kcal min(-1) ; P < 0.001) and fasting (Fed, 0.87 ± 0.51 kcal min(-1) ; Fast, 1.30 ± 0.37 kcal min(-1) , P < 0.05). SIRT3 gene expression decreased (P < 0.05) after both exercise (-8%) and fasting (-19%); however, SIRT3 whole muscle protein content was unaltered after fasting. No changes were observed in SIRT3 mitochondrial localization following either exercise or fasting. Fasting also decreased the Vmax of glutamate [80 ± 43 versus 50 ± 21 pmol s(-1) (mg dry weight)(-1) ; P < 0.05]. These findings suggest that SIRT3 does not appear to be regulated by changes in mitochondrial localization at the time points measured in the present study in response to cellular energy stress in human skeletal muscle.

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“…; Lu et al . ). Following fasting, altered SIRT3 expression may contribute to the regulation of fatty acid oxidation and oxidative metabolism in murine skeletal muscle (Shi et al .…”

Section: Introductionmentioning

confidence: 97%

SIRT3 gene expression but not SIRT3 subcellular localization is altered in response to fasting and exercise in human skeletal muscle

Edgett

Hughes

Matusiak

et al. 2016

Experimental Physiology

View full text Add to dashboard Cite

show abstract

“…While the extent of LCAD hyperacetylation was lower in Alrob's study (?50 %) compared to our study (?400 %), the explanation for different results in probably identical SIRT3 -/-mice with similarly low fat content (12 % by calories) in the food remains to be elucidated. Of note, Lu and colleagues recently reported that increased acetylation of the K56 residue of Hsp10 in the absence of SIRT3 may alter the binding affinities between Hsp10 and Hsp60, which in turn may enhance the capacity to appropriately fold MCAD, resulting in increased enzyme activity and overall fatty acid oxidation [29]. Thus, besides regulating energy metabolic rates by directly modulating metabolic enzyme acetylation, additional mechanisms seem to exist by which SIRT3 may regulate energy metabolism, which have not been investigated in our study or the study by Alrob and colleagues.…”

Section: Discussionmentioning

confidence: 99%

SIRT3 deficiency impairs mitochondrial and contractile function in the heart

et al. 2015

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Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography. Four weeks following transverse aortic constriction, ejection fraction was further decreased in SIRT3(-/-) mice compared to WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis. In isolated working hearts, a decrease in cardiac function in SIRT3(-/-) mice was accompanied by a decrease in palmitate oxidation, glucose oxidation, and oxygen consumption, whereas rates of glycolysis were increased. Respiratory capacity and ATP synthesis were decreased in cardiac mitochondria of SIRT3(-/-) mice. HPLC measurements revealed a decrease of the myocardial ATP/AMP ratio and of myocardial energy charge. Using LC-MS/MS, we identified increased acetylation of 84 mitochondrial proteins, including 6 enzymes of fatty acid import and oxidation, 50 subunits of the electron transport chain, and 3 enzymes of the tricarboxylic acid cycle. Lack of SIRT3 impairs mitochondrial and contractile function in the heart, likely due to increased acetylation of various energy metabolic proteins and subsequent myocardial energy depletion.

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“…Also uncertain is whether global shifts in lysine acetylation have a physiologically relevant impact on cellular function, especially considering that many of these events appear to occur at low stoichiometry (Baeza et al, 2014; Weinert et al, 2015). Nonetheless, a growing number of studies using site-directed mutagenesis strategies show that at least some of these modifications alter activity of mitochondrial proteins, mostly in a negative direction (Hallows et al, 2006; Hallows et al, 2011; Hirschey et al, 2010; Still et al, 2013), although gain-of-function acetylation events have been reported (Fernandes et al, 2015; Lu et al, 2015). Lysine acetylation has also been linked to nutrient control of autophagy and mitophagy (Webster et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins

et al. 2016

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Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle-specific deficiency of carnitine acetyltransferase (CrAT), an enzyme that buffers the mitochondrial acetyl-CoA pool by converting short-chain acyl-CoAs to their membrane permeant acylcarnitine counterparts. CrAT deficiency increased tissue acetyl-CoA levels and susceptibility to diet-induced AcK of broad-ranging mitochondrial proteins, coincident with diminished whole body glucose control. Sub-compartment acetylproteome analyses of muscles from obese mice and humans showed remarkable overrepresentation of mitochondrial matrix proteins. These findings reveal roles for CrAT and L-carnitine in modulating the muscle acetylproteome and provide strong experimental evidence favoring the nonenzymatic carbon pressure model of mitochondrial AcK.

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Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Cited by 49 publications

References 47 publications

SIRT3 gene expression but not SIRT3 subcellular localization is altered in response to fasting and exercise in human skeletal muscle

SIRT3 gene expression but not SIRT3 subcellular localization is altered in response to fasting and exercise in human skeletal muscle

SIRT3 deficiency impairs mitochondrial and contractile function in the heart

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins

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