Figure 2.
Molecular mechanisms of the effect of pharmacological interventions on autophagy/mitophagy. TAT-Beclin 1 competitively inhibits the interaction between endogenous Beclin 1 and its negative regulator, GAPR-1, thereby mobilizing Beclin 1 to stimulate autophagy.67 Spermidine stimulates autophagy by inhibiting cytosolic EP300 acetyltransferase.68 Furthermore, spermidine facilitates translocation of FOXO from the cytosol to nucleus and provokes epigenetic reprogramming through inhibition of histone acetyltransferases in the nucleus, thereby activating transcription of autophagy-related genes.69 Spermidine also promotes hypusination of translational factor eIF5A, which uniquely contains the unusual amino acid hypusine, in memory B cells.70 This post-translational modification of eIF5A makes the formation of the first peptide bonds more effective in the translation of TFEB mRNA. Trehalose promotes translocation of TFEB from the cytosol to nucleus, thereby inducing autophagy-related genes in macrophages and cardiomyocytes.64,71 Trehalase expressed in the intestine in mice and humans can degrade Trehalose.64 The detailed mechanism by which Urolithin A induces autophagy/mitophagy has yet to be clarified. Induction of autophagy/mitophagy-related genes and phosphorylation of AMPK were observed after treatment with Urolithin A in C2C12 myoblasts and skeletal muscles in mice and humans.65,66