GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy

Scott, Iain; Webster, Bruce; Chan, Carmen K. M.; Okonkwo, Joshua U.; Kim, Han; Sack, Michael N.

doi:10.1074/jbc.m113.521641

Cited by 109 publications

(124 citation statements)

References 27 publications

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“…Within mitochondria, the sirtuin Sirt3 is the major NAD 1 -dependent deacetylase (5) Recently, GCN5L1 was identified as a component of the mitochondrial acetylation machinery and proposed to be the opponent of Sirt3 (6,7). It is well established that Sirt3 is involved in the metabolic reprogramming of mitochondria in response to alterations in nutrient supply (8).…”

Section: Introductionmentioning

confidence: 99%

Retracted: Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance

et al. 2014

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Changes in nutrient supply require global metabolic reprogramming to optimize the utilization of the nutrients. Mitochondria as a central component of the cellular metabolism play a key role in this adaptive process. Since mitochondria harbor their own genome, which encodes essential enzymes, mitochondrial protein synthesis is a determinant of metabolic adaptation. While regulation of cytoplasmic protein synthesis in response to metabolic challenges has been studied in great detail, mechanisms which adapt mitochondrial translation in response to metabolic challenges remain elusive. Our results suggest that the mitochondrial acetylation status controlled by Sirt3 and its proposed opponent GCN5L1 is an important regulator of the metabolic adaptation of mitochondrial translation. Moreover, both proteins modulate regulators of cytoplasmic protein synthesis as well as the mitonuclear protein balance making Sirt3 and GCN5L1 key players in synchronizing mitochondrial and cytoplasmic translation. Our results thereby highlight regulation of mitochondrial translation as a novel component in the cellular nutrient sensing scheme and identify mitochondrial acetylation as a new regulatory principle for the metabolic competence of mitochondrial protein synthesis.

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Section: Introductionmentioning

confidence: 99%

Retracted: Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance

et al. 2014

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“…One of the possibilities could be that GCN5 and SIRT6-mediated deacetylation of PGC-1␣ potentially contributes to maturational increase in fatty acid oxidation, and inhibiting GCN5L1 alone may not be sufficient to suppress overall fatty acid oxidation rates. In addition, nuclear expression of TFEB was dramatically downregulated in 21-day-old hearts as opposed to an increase in GCN5L1 expression, suggesting that maturational alterations in mitochondrial biogenesis mediated by GCN5L1 are partly due to the suppression of mitochondrial degradation via autophagy through TFEB (53). Collectively, the increase in overall acetylation is associated with the age-dependent increase in cardiac fatty acid oxidation, whereas GCN5L1 along with other factors contribute to this process during maturation.…”

Section: H354mentioning

confidence: 78%

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Fukushima

Alrob

Zhang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, Rebeyka IM, Kantor PF, Lopaschuk GD. Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol 311: H347-H363, 2016. First published June 3, 2016; doi:10.1152/ajpheart.00900.2015.-Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid ␤-oxidation rates increased in 21-day vs. 1-and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and ␤-hydroxyacylCoA dehydrogenase (␤-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid ␤-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and ␤-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator-1␣, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxiainducible factor-1␣, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.Listen to this article's corresponding podcast at http://ajpheart.podbean. com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/. myocardial fatty acid oxidation; lysine acetylation; lysine succinylation; newborn heart NEW & NOTEWORTHYThe present study is the first showing that alterations in acetylation and succinylation control of metabolic enzymes contribute to the dramatic shift in cardiac energy metabolism from glycolysis to fatty acid ␤-oxidation seen during maturation. Our results suggest that lysine acetylation enhances cardiac fatty acid ␤-oxidation and inhibits glycolysis during maturation.OVER 1% OF NEWBORNS ARE DIAGNOSED with congenital heart disease (CHD), with one-third of these needing surgery within the first months of life (36). Despite the major advance...

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“…Immature lysosomes accumulate, and the function of lysosomes in autophagy is impaired in snapin-deficient neurons (17). Likewise, autophagosomes accumulate in BLOS1 knock-out (KO) mouse embryonic fibro-blasts (MEFs), suggesting that BLOC-1 functions in autophagy (18). It must be emphasized that the above-mentioned functions may be attributable to specific BLOC-1 subunits rather than the whole BLOC-1 complex.…”

Section: Bloc-1mentioning

confidence: 99%

Biogenesis of Lysosome-related Organelles Complex-1 Subunit 1 (BLOS1) Interacts with Sorting Nexin 2 and the Endosomal Sorting Complex Required for Transport-I (ESCRT-I) Component TSG101 to Mediate the Sorting of Epidermal Growth Factor Receptor into Endosomal Compartments

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: EGFR lysosomal trafficking process is important for the modulation of EGF signaling. Results: Delayed EGFR degradation in BLOS1 knockdown cells is restored by the overexpressed BLOS1 fragment that interacts with both SNX2 and TSG101. Conclusion: BLOS1 mediates EGFR lysosomal trafficking. Significance: Enhancement of EGFR lysosomal degradation will be effective in the treatment of cancer or lung fibrosis.

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GCN5-like Protein 1 (GCN5L1) Controls Mitochondrial Content through Coordinated Regulation of Mitochondrial Biogenesis and Mitophagy

Cited by 109 publications

References 27 publications

Retracted: Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance

Retracted: Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance

Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

Biogenesis of Lysosome-related Organelles Complex-1 Subunit 1 (BLOS1) Interacts with Sorting Nexin 2 and the Endosomal Sorting Complex Required for Transport-I (ESCRT-I) Component TSG101 to Mediate the Sorting of Epidermal Growth Factor Receptor into Endosomal Compartments

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