α-Lipoic acid promotes α-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy

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...

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Veröffentlicht in:Biochemical journal 2016-06, Vol.473 (12), p.1821-1830
Hauptverfasser: Stoner, Michael W, Thapa, Dharendra, Zhang, Manling, Gibson, Gregory A, Calderon, Michael J, St Croix, Claudette M, Scott, Iain
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container_end_page 1830
container_issue 12
container_start_page 1821
container_title Biochemical journal
container_volume 473
creator Stoner, Michael W
Thapa, Dharendra
Zhang, Manling
Gibson, Gregory A
Calderon, Michael J
St Croix, Claudette M
Scott, Iain
description 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.
doi_str_mv 10.1042/BCJ20160281
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Acetyl Coenzyme A - metabolism
Acetylation - drug effects
Acetyltransferases - metabolism
Animals
Autophagy - drug effects
Cercopithecus aethiops
COS Cells
Hep G2 Cells
Histone Deacetylase Inhibitors - pharmacology
Humans
Microscopy, Confocal
Mitochondria - drug effects
Mitochondria - metabolism
Signal Transduction - drug effects
Thioctic Acid - pharmacology
Tubulin - metabolism
title α-Lipoic acid promotes α-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy
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