Astroglial biotin deprivation inhibits autophagy to elicit endoplasmic reticulum stress by uncoupling branched chain amino acids mtorc1 role in lipogenesis in the aging brain

Abstract

Autophagy delays the onset of stress in the endoplasmic reticulum (ER) by recycling of cellular debris. Nevertheless, the cues eliciting autophagy during aging under the emergence of ER stress and their dysregulation remain elusive. Amino acids, especially Branched-Chain Amino Acids (BCAA), accumulate in cells once ER stress inhibits protein synthesis. The BCAA mimics satiety to inhibit autophagy through mechanistic targets of activation of rapamycin complex 1 (mTORC1) while, in contrast, their catabolism supplements de novo lipogenesis for autophagosome membranes formation. It is thus hypothesized that promoting BCAA utilization would induce autophagy to alleviate ER stress. However, except for protein synthesis, the rest of the lipogenesis and the rest of BCAA relies on the co-enzyme biotin. Therefore, in the aging brain of Wistar rats, levels of biotinylated newlinecarboxylases and lipids were examined. Despite the increased levels of biotinylated carboxylases and lipids, BCAA accumulated in the aging brain. Since astrocytes are the primary site of BCAA and lipid metabolism, and the increased expression of Glial Fibrillary Acid Protein (GFAP) denotes astroglial ER stress, co-localization studies have been conducted to determine the extent of biotinylation in GFAP positive cells. While the overall biotin intensity has been higher in aged brain slices, the specific astrocyte decrease in biotinylation is attributed to BCAA accumulation, mTORC1 overactivation, autophagy inhibition, and ER stress in the aging brain. newline newline