Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA-mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain.
Dhasarathan GanesanAnand Ramaian SanthaseelaSudarshana RajasekaranSenthilraja SelvamTamilselvan JayaveluPublished in: Journal of neurochemistry (2020)
Autophagy delays the onset of endoplasmic reticulum (ER) stress by recycling cellular debris. However, the cues that elicit autophagy under the emergence of ER stress and their dysregulation during aging remains obscure. Amino acids, notably branched-chain amino acids (BCAA), get accumulated in the cells once protein synthesis is inhibited by ER stress. The BCAA mimic satiety to inhibit autophagy via mechanistic targets of rapamycin complex 1 (mTORC1) activation and, in contrast, their catabolism supplements de novo lipogenesis for the formation of autophagosome membranes. Thus promoting BCAA utilization is hypothesized to induce autophagy to alleviate ER stress. Nevertheless, except protein synthesis, the rest of BCAA utilization and lipogenesis depends on the co-enzyme biotin. Hence, the levels of biotinylated carboxylases and lipids were assessed in the aging brain of Wistar rats. Despite the increased levels of biotinylated carboxylases and lipids, the aging brain accumulates BCAA. Since astrocytes are the primary site of BCAA and lipid metabolism and the increased expression of glial fibrillary acidic protein (GFAP) denotes astroglial ER stress, co-localization studies were performed to determine the extent of biotinylation in GFAP positive cells. 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.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- cell death
- signaling pathway
- resting state
- oxidative stress
- white matter
- amino acid
- cell cycle arrest
- functional connectivity
- endoplasmic reticulum
- cerebral ischemia
- fatty acid
- metabolic syndrome
- poor prognosis
- magnetic resonance
- insulin resistance
- binding protein
- cell proliferation
- brain injury
- ionic liquid
- subarachnoid hemorrhage
- spinal cord injury
- pi k akt
- protein protein