Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA‐mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain

Abstract

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. image

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“…68 Astrocytes mainly utilize BCAAs (such as leucine, isoleucine, and valine) to synthesize lipids and glutamate to support the structure and function of neurons. 69 Studies have found that BCAA can be used as anti-inflammatory agents. 70 Acute and chronic supplementation of BCAA exhibits anti-inflammatory effects in LPS-stimulated macrophages.…”

“…Branched-chain amino acids (BCAAs) can regulate various cellular functions such as immunity, metabolism, and gene expression . Astrocytes mainly utilize BCAAs (such as leucine, isoleucine, and valine) to synthesize lipids and glutamate to support the structure and function of neurons . Studies have found that BCAA can be used as anti-inflammatory agents .…”

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

“…The mTOR is a master regulator of cellular metabolism, which also plays a crucial role in regulating autophagy. Activation of mTORC1 can lead to autophagy inhibition through the phosphorylation of multiple proteins ( 27 ). Our Western blotting analysis results demonstrated that hiPSC-EC-EV could reduce p-mTOR expression in HUVECs in vitro ( Figure 7B ).…”

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“…Prolonged exposure to a diet high in BCAAs could result in hyperphagia, obesity, and a shorter lifespan (84). Notably, astrocytic biotinylation and increased BCAAs accumulate in the aging cerebral cortex, which may be related to the inhibition of autophagy and overactivation of the mTOR complex (85). However, restricting BCAAs intake has been shown to promote metabolism, delay aging, and prevent disease (86).…”