Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy

Guillermo Mariño, Federico Pietrocola, Yongli Kong, Tobias Eisenberg, Joseph A Hill, Frank Madeo, Guido Kroemer

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

It has been a longstanding problem to identify specific and efficient pharmacological modulators of autophagy. Recently, we found that depletion of acetyl-coenzyme A (AcCoA) induced autophagic flux, while manipulations designed to increase cytosolic AcCoA efficiently inhibited autophagy. Thus, the cell permeant ester dimethyl α-ketoglutarate (DMKG) increased the cytosolic concentration of α-ketoglutarate, which was converted into AcCoA through a pathway relying on either of the 2 isocitrate dehydrogenase isoforms (IDH1 or IDH2), as well as on ACLY (ATP citrate lyase). DMKG inhibited autophagy in an IDH1-, IDH2- and ACLY-dependent fashion in vitro, in cultured human cells. Moreover, DMKG efficiently prevented autophagy induced by starvation in vivo, in mice. Autophagy plays a maladaptive role in the dilated cardiomyopathy induced by pressure overload, meaning that genetic inhibition of autophagy by heterozygous knockout of Becn1 suppresses the pathological remodeling of heart muscle responding to hemodynamic stress. Repeated administration of DMKG prevents autophagy in heart muscle responding to thoracic aortic constriction (TAC) and simultaneously abolishes all pathological and functional correlates of dilated cardiomyopathy: hypertrophy of cardiomyocytes, fibrosis, dilation of the left ventricle, and reduced contractile performance. These findings indicate that DMKG may be used for therapeutic autophagy inhibition.

Original languageEnglish (US)
Pages (from-to)930-932
Number of pages3
JournalAutophagy
Volume10
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Acetyl-coenzyme A
  • Dilated cardiopathy
  • Macroautophagy

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Mariño, G., Pietrocola, F., Kong, Y., Eisenberg, T., Hill, J. A., Madeo, F., & Kroemer, G. (2014). Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy. Autophagy, 10(5), 930-932. https://doi.org/10.4161/auto.28235