Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes
Autor: | Ming Zhao, Xiaolixue Qiu, Haiyan Huang, Jessica A. Deis, Hong Guo, Qi Qun Tang, Xiaoli Chen |
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Rok vydání: | 2016 |
Předmět: |
Lipopolysaccharides
0301 basic medicine Autophagosome Vesicular Transport Proteins Mitochondrion Biochemistry Cathepsin B 0302 clinical medicine Endocrinology hemic and lymphatic diseases Mitophagy Adipocytes Research Articles Chemistry Toll-Like Receptors NF-kappa B RNA-Binding Proteins Niemann-Pick Disease Type C Mitochondria Cell biology medicine.anatomical_structure Phosphorylation Niemann-Pick disease Microtubule-Associated Proteins Signal Transduction obesity • lysosome congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Mitochondrial DNA MAP Kinase Signaling System QD415-436 Cell Line 03 medical and health sciences Internal medicine Lysosome Autophagy medicine Humans Glycoproteins Tumor Necrosis Factor-alpha nutritional and metabolic diseases Cell Biology 030104 developmental biology inflammation toll-like receptor Carrier Proteins Lysosomes 030217 neurology & neurosurgery |
Zdroj: | Journal of Lipid Research, Vol 57, Iss 9, Pp 1644-1658 (2016) |
ISSN: | 0022-2275 |
DOI: | 10.1194/jlr.m066522 |
Popis: | In this study, we investigated the role and mechanism of Niemann-Pick type C (NPC)2 in regulating lysosomal activity, mitophagy, and mitochondrial function in adipocytes. We found that knocking down NPC2 impaired lysosomal activity, as evidenced by the reduced mature cathepsin B, the increased accumulation of light chain 3 (LC3) and p62, and the decreased autophagic flux. In NPC2-knockdown (kd) adipocytes, the starvation-induced conversion of LC3-I to LC3-II was abolished. More interestingly, the majority of NPC2 was found in the mitochondrial fraction, and NPC2 deficiency led to impaired autophagic flux and decreased induction of LC3-II in the mitochondrial fraction during mitochondrial stress. Moreover, cellular respiration profiling revealed that NPC2-kd adipocytes had significantly decreased basal/maximal respiration and mitochondrial gene expression compared with scrambled cells, suggesting mitochondrial dysfunction. Additionally, we found that the mitochondrial recruitment of LC3-II induced by lipopolysaccharide (LPS), but not TNFα, was blunted in NPC2-kd adipocytes. Most intriguingly, NPC2-kd selectively diminished LPS-induced NFκB and ERK1/2 phosphorylation and the expression of pro-inflammatory genes, indicating that toll-like receptor signaling activation is impaired in the absence of NPC2. Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophagy, mitochondrial quality control, and mitochondrial function. |
Databáze: | OpenAIRE |
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