Dual role of Biotin in regulating Autophagy

Both excess of biotin and it’s deficiency seem to inhibit autophagy.

Reduced biotinylation inhibits autophagy

Although total biotin intensity was higher in aged brain slices, the astrocytes specific decrease in biotinylation is attributed to BCAA accumulation, mTORC1 overactivation, autophagy inhibition, and ER stress in the aging brain. 

The ER stress in primary astrocytes using tunicamycin also mimic the in vivo phenotype. Biotin supplementation ameliorated the changes observed in vitro, corroborating the significance of astrocytes biotin availability to promote autophagy under ER stress in aging" (R1)

Note that in that paper it was found that the level of biotin was elevated, but biotinylation of proteins was reduced, which points to either poor function of HoloCarboxylase Synthetase enzyme or poor cellular uptake (?).

Excess of biotin inhibits autophagy

Biotin restricts cellular signaling associated with protein synthesis without altering total protein content. The decline in autophagy elicits endoplasmic reticulum stress to inhibit protein synthesis by eIF2α phosphorylation possibly via accumulation of misfolded/long-lived proteins.

Furthermore, the compensatory increase in Unc51 like autophagy activating kinase 1 possibly competes with eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6kinase phosphorylation by mechanistic targets of rapamycin complex 1 to uncouple its effect on protein synthesis. 

In conclusion, autophagy inhibition by biotin uncouples protein synthesis to promote lipogenesis by eliciting endoplasmic reticulum stress and differential phosphorylation of mechanistic targets of rapamycin complex 1 substrates. (R2)

the supplementation of biotin is anticipated to spare dietary amino acids to sensitize insulin signaling and to sustain both lipid and protein synthesis via mTORC1 activation.

In contrast, biotin accelerates insulin-induced adipogenesis by inhibiting autophagy. This uncouples adipocyte protein synthesis from lipogenesis via differential phosphorylation of mTORC1 substrates and ER stress without significant alterations in intracellular levels of amino acids. (R2)