Lysine acetylation is tightly coupled to the nutritional status of the cell, as the availability of its cofactor, acetyl-CoA, fluctuates with changing metabolic conditions. Recent studies have demonstrated that acetyl-CoA levels act as an indicator of cellular nourishment, and increased abundance of this metabolite can block the induction of cellular recycling programmes. In the present study we investigated the cross-talk between mitochondrial metabolic pathways, acetylation and autophagy, using chemical inducers of mitochondrial acetyl-CoA production. Treatment of cells with α-lipoic acid (αLA), a cofactor of the pyruvate dehydrogenase complex, led to the unexpected hyperacetylation of α-tubulin in the cytosol. This acetylation was blocked by pharmacological inhibition of mitochondrial citrate export (a source for mitochondria-derived acetyl-CoA in the cytosol), was dependent on the α-tubulin acetyltransferase (αTAT) and was coupled to a loss in function of the cytosolic histone deacetylase, HDAC6. We further demonstrate that αLA slows the flux of substrates through autophagy-related pathways, and severely limits the ability of cells to remove depolarized mitochondria through PTEN-associated kinase 1 (PINK1)-mediated mitophagy.
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K-Ras4B membrane-anchored dimers in the cell. Dimerization can take place through helical (left) and beta-sheet (right) interfaces. The major (front) and minor (back) conformations are shown. For further details please see pp. 1719–1732. Image kindly provided by Ruth Nussinov. - PDF Icon PDF LinkFront Matter
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Research Article|
June 10 2016
α-Lipoic acid promotes α-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy
Michael W. Stoner;
Michael W. Stoner
*Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Dharendra Thapa;
Dharendra Thapa
*Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Manling Zhang;
Manling Zhang
*Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Gregory A. Gibson;
Gregory A. Gibson
†Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Michael J. Calderon;
Michael J. Calderon
†Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Claudette M. St. Croix;
Claudette M. St. Croix
†Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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Iain Scott
Iain Scott
1
*Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
1To whom correspondence should be addressed (email scotti2@upmc.edu).
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Publisher: Portland Press Ltd
Received:
July 03 2015
Revision Received:
April 19 2016
Accepted:
April 20 2016
Accepted Manuscript online:
April 20 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (12): 1821–1830.
Article history
Received:
July 03 2015
Revision Received:
April 19 2016
Accepted:
April 20 2016
Accepted Manuscript online:
April 20 2016
Citation
Michael W. Stoner, Dharendra Thapa, Manling Zhang, Gregory A. Gibson, Michael J. Calderon, Claudette M. St. Croix, Iain Scott; α-Lipoic acid promotes α-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy. Biochem J 15 June 2016; 473 (12): 1821–1830. doi: https://doi.org/10.1042/BCJ20160281
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