Complete neural stem cell (NSC) neuronal differentiation requires a branched chain amino acids-induced persistent metabolic shift towards energy metabolism

被引：40

作者：

Bifari, Francesco ^{[1
]}

Dolci, Sissi ^{[2
]}

Bottani, Emanuela ^{[2
,3
]}

Pino, Annachiara ^{[2
]}

Di Chio, Marzia ^{[2
]}

Zorzin, Stefania ^{[2
]}

Ragni, Maurizio ^{[4
]}

Zamfir, Raluca Georgiana ^{[2
]}

Brunetti, Dario ^{[4
]}

Bardelli, Donatella ^{[5
,6
]}

Delfino, Pietro ^{[7
]}

Cattaneo, Maria Grazia ^{[8
]}

Bordo, Roberta ^{[1
]}

Tedesco, Laura ^{[4
]}

Rossi, Fabio ^{[4
]}

Bossolasco, Patrizia ^{[5
,6
]}

Corbo, Vincenzo ^{[7
]}

Fumagalli, Guido ^{[2
]}

Nisoli, Enzo ^{[4
]}

Valerio, Alessandra ^{[3
]}

Decimo, Ilaria ^{[2
]}

机构：

[1] Univ Milan, Dept Med Biotechnol & Translat Med, Lab Cell Metab & Regenerat Med, Via Vanvitelli 32, I-20129 Milan, Italy

[2] Univ Verona, Sect Pharmacol, Dept Diagnost & Publ Hlth, Ple Scuro 10, I-37134 Verona, Italy

[3] Univ Brescia, Dept Mol & Translat Med, Brescia, Italy

[4] Univ Milan, Dept Med Biotechnol & Translat Med, Ctr Study & Res Obes, Milan, Italy

[5] IRCCS Ist Auxol Italiano, Dept Neurol, Milan, Italy

[6] IRCCS Ist Auxol Italiano, Lab Neurosci, Milan, Italy

[7] Univ Verona, Dept Diagnost & Publ Hlth, Sect Pathol Anat, Verona, Italy

[8] Univ Milan, Dept Med Biotechnol & Translat Med, Via Vanvitelli 32, I-20129 Milan, Italy

来源：

PHARMACOLOGICAL RESEARCH | 2020年 / 158卷

关键词：

Neuronal differentiation; Neural stem cells; Human iPSC; Cell metabolism; ROS metabolism; Metabolic rewiring; mTORC1; MITOCHONDRIAL BIOGENESIS; FUSION; MTOR; PATHWAY; COST; QUANTIFICATION; HOMEOSTASIS; ACTIVATION; MECHANISMS; MORPHOLOGY;

D O I：

10.1016/j.phrs.2020.104863

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Neural stem cell (NSC) neuronal differentiation requires a metabolic shift towards oxidative phosphorylation. We now show that a branched-chain amino acids-driven, persistent metabolic shift toward energy metabolism is required for full neuronal maturation. We increased energy metabolism of differentiating neurons derived both from murine NSCs and human induced pluripotent stem cells (iPSCs) by supplementing the cell culture medium with a mixture composed of branched-chain amino acids, essential amino acids, TCA cycle precursors and cofactors. We found that treated differentiating neuronal cells with enhanced energy metabolism increased: i) total dendritic length; ii) the mean number of branches and iii) the number and maturation of the dendritic spines. Furthermore, neuronal spines in treated neurons appeared more stable with stubby and mushroom phenotype and with increased expression of molecules involved in synapse formation. Treated neurons modified their mitochondrial dynamics increasing the mitochondrial fusion and, consistently with the increase of cellular ATP content, they activated cellular mTORC1 dependent p70S6 K1 anabolism. Global transcriptomic analysis further revealed that treated neurons induce Nrf2 mediated gene expression. This was correlated with a functional increase in the Reactive Oxygen Species (ROS) scavenging mechanisms. In conclusion, persistent branched-chain amino acids-driven metabolic shift toward energy metabolism enhanced neuronal differentiation and antioxidant defences. These findings offer new opportunities to pharma-cologically modulate NSC neuronal differentiation and to develop effective strategies for treating neurodegenerative diseases.

引用

页数：18

共 93 条

[61] Golgi-derived PI(4)P-containing vesicles drive late steps of mitochondrial division [J].