title: Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway.
abstract: Autophagy is a double-edged sword in cellular survival, but its effects on nucleus pulposus (NP) cells are yet to be clarified. This study explored the role and molecular mechanisms of autophagy in the survival of NP cells under nutrient deprivation. Glucose limitation induced time-dependent morphological changes, proteoglycan degradation, and apoptosis in NP cells. Glucose deprivation triggered the activation of early-stage autophagy, evident as increases in LC3-II and ATG12-ATG5 expression and the number of GFP-LC3 puncta. Importantly, at early time points, the autophagy inhibitor 3-MA significantly enhanced the apoptosis of NP cells, suggesting that early-stage autophagy protects cells against glucose deprivation. Interestingly, the p-eIF2α/ATF4 unfolded protein response pathway was activated in NP cells deprived of glucose, and a deficiency in ATF4 attenuated the activation of early-stage autophagy and increased apoptosis. ATF4 silencing also inhibited the late-stage accumulation of reactive oxygen species (ROS) and apoptosis. Together, our results demonstrate an interplay between endoplasmic reticulum stress, ROS production, and the early-stage autophagy induced by glucose deprivation in NP cells. These findings may provide a therapeutic strategy for the treatment of degenerative intervertebral disc disease.
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Hongze
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Mintao
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China.
authors.forename: Anli
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China. Electronic address: lxd818@163.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000070614:Nucleus Pulposus / Q000166:cytology / Q000187:drug effects*
chemical_list: C497109:ATF4 protein, human; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; D005947:Glucose
keywords: Apoptosis; Autophagy; Glucose deprivation; Nucleus pulposus cells