167 450

Cited 11 times in

Autophagy induction by tetrahydrobiopterin deficiency.

SS, Kwak; J, Suk; JH, Choi; S, Yang; JW, Kim; S, Sohn; JH, Chung; YH, Hong; DH, Lee; JK, Ahn; H, Min; YM, Fu; GG, Meadows; CO, Joe
Autophagy, 7(11):1323-1334, 2011
Journal Title
Tetrahydrobiopterin (BH₄) deficiency is a genetic disorder associated with a variety of metabolic syndromes such as phenylketonuria (PKU). In this article, the signaling pathway by which BH₄ deficiency inactivates mTORC1 leading to the activation of the autophagic pathway was studied utilizing BH₄-deficient Spr(-/-) mice generated by the knockout of the gene encoding sepiapterin reductase (SR) catalyzing BH₄ synthesis. We found that mTORC1 signaling was inactivated and autophagic pathway was activated in tissues from Spr(-/-) mice. This study demonstrates that tyrosine deficiency causes mTORC1 inactivation and subsequent activation of autophagic pathway in Spr(-/-) mice. Therapeutic tyrosine diet completely rescued dwarfism and mTORC1 inhibition but inactivated autophagic pathway in Spr(-/-) mice. Tyrosine-dependent inactivation of mTORC1 was further supported by mTORC1 inactivation in Pah(enu2) mouse model lacking phenylalanine hydroxylase (Pah). NIH3T3 cells grown under the condition of tyrosine restriction exhibited autophagy induction. However, mTORC1 activation by RhebQ64L, a positive regulator of mTORC1, inactivated autophagic pathway in NIH3T3 cells under tyrosine-deficient conditions. In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH₄ deficiency.
MeSH terms
Alcohol Oxidoreductases/deficiency/metabolismAnimals*Autophagy/drug effectsBiopterin/*analogs & derivatives/deficiency/pharmacology/therapeutic useChildDown-Regulation/drug effectsFemaleHumansInfantLiver/drug effects/pathology/ultrastructuMaleMiceMonomeric GTP-Binding Proteins/metabolismNIH 3T3 CellsNeuropeptides/metabolismPhenylalanine/metabolismPhenylalanine Hydroxylase/metabolismPhenylketonurias/drug therapy/pathologyProteins/metabolismTyrosine/deficiency/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
AJOU Authors
손, 성향
Full Text Link
Files in This Item:
There are no files associated with this item.
RIS (EndNote)
XLS (Excel)


해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.