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 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.
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Michael W
MW
Stoner
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Dharendra
D
Thapa
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Manling
M
Zhang
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Gregory A
GA
Gibson
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Michael J
MJ
Calderon
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
Claudette M
CM
St Croix
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A. scotti2@upmc.edu.
Iain
I
Scott
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*
D056572:Histone Deacetylase Inhibitors; D014404:Tubulin; D000105:Acetyl Coenzyme A; D008063:Thioctic Acid; D000123:Acetyltransferases; C049182:alpha-tubulin acetylase
autophagy; histone deacetylase 6 (HDAC6); hyperacetylation; mitochondria; mitophagy; α-lipoic acid; α-tubulin acetylation; α-tubulin acetyltransferase (αTAT)