Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A

Abstract

Acetyl-coenzyme A (AcCoA) is a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism. Here we show that nutrient starvation causes rapid depletion of AcCoA. AcCoA depletion entailed the commensurate reduction in the overall acetylation of cytoplasmic proteins, as well as the induction of autophagy, a homeostatic process of self-digestion. Multiple distinct manipulations designed to increase or reduce cytosolic AcCoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice. Moreover, maintenance of high AcCoA levels inhibited maladaptive autophagy in a model of cardiac pressure overload. Depletion of AcCoA reduced the activity of the acetyltransferase EP300, and EP300 was required for the suppression of autophagy by high AcCoA levels. Altogether, our results indicate that cytosolic AcCoA functions as a central metabolic regulator of autophagy, thus delineating AcCoA-centered pharmacological strategies that allow for the therapeutic manipulation of autophagy.

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

“…This percentage raised to 77% (14 out of 18) when the mice were subjected to starvation regimen. Importantly, when starvation was combined with injection of dimethyl α-ketoglutarate (DMKG), which inhibits starvation-induced autophagy, 24,25 this percentage dropped to 22% (4 out of 18), indicating a significant immunosuppressive effect of DMKG (Figure 1B). These results confirm that starvation can mediate immunostimulatory effects.…”

Metabolic effects of fasting on human and mouse blood in vivo

“…Starvation of mice reduces the overall level of protein acetylation in the heart and in the muscle, 21,26 a phenomenon that is related to the known capacity of starvation to deplete acetylCoA 21 and to activate the deacetylase activity of sirtuins. 27,28 Therefore, we investigated the effects of starvation on protein acetylation levels by immunofluorescence staining of permeabilized and fixed leukocytes with an antibody specific for protein containing acetylated lysine residues.…”

“…21,22,32 For this, we first performed a series of immunoblots to detect the lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 b), knowing that the autophagy-associated, covalent linkage of LC3B to phosphatidylethanolamine causes an increase in its electrophoretic mobility (the so-called LC3B-I!LC3B-II conversion). 33 In addition we measured the autophagy-dependent degradation of SQSTM1/p62, a receptor and scaffold protein interacting with LC3 and ubiquitinated proteins (through a specific LC3-interacting region [LIR] and ubiquitin-associated [UBA] domain, respectively).…”

“…19 Starvation leads to a global decrease in protein acetylation in cells due to the combined increase in the enzymatic activity of protein deacetylases (in particular sirtuins) and the decrease in the activity of acetyltransferases (in particular EP300 [E1A binding protein p300]). [20][21][22][23] Based on these premises, we decided to measure protein acetylation and autophagy in leukocytes from mice or healthy persons in conditions of obligatory or voluntary starvation, respectively. Here, we report that we were able to measure protein deacetylation in leukocytes from starved mice and healthy volunteers that agreed to start a period of up to 5 d of fasting.…”

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…Spermidine induces autophagy through the inhibition of several acetyltransferases [7], including EP300 [21], one of the main negative regulators of autophagy [22]. Its potency has been recently quantified to be equivalent to that of rapamycin [23], an FDA-approved immunosuppressant with protective and autophagy-stimulatory properties [24,25].…”