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

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.

journal_name

Autophagy

journal_title

Autophagy

authors

Mariño G,Pietrocola F,Kong Y,Eisenberg T,Hill JA,Madeo F,Kroemer G

doi

10.4161/auto.28235

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

930-2

issue

5

eissn

1554-8627

issn

1554-8635

pii

28235

journal_volume

10

pub_type

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