NPC1 is required for postnatal islet β cell differentiation by maintaining mitochondria turnover
NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet...
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Published in | Theranostics Vol. 14; no. 5; pp. 2058 - 2074 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Australia
Ivyspring International Publisher
01.01.2024
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Subjects | |
Online Access | Get full text |
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Summary: | NPC1 is a protein localized on the lysosome membrane regulating intracellular cholesterol transportation and maintaining normal lysosome function. GWAS studies have found that
variants in T2D was a pancreatic islet expression quantitative trait locus, suggesting a potential role of NPC1 in T2D islet pathophysiology.
Two-week-old
mice and wild type littermates were employed to examine pancreatic β cell morphology and functional changes induced by loss of
. Single cell RNA sequencing was conducted on primary islets.
Min6 cell line was generated using CRISPR/Cas9 gene editing. Seahorse XF24 was used to analyze primary islet and Min6 cell mitochondria respiration. Ultra-high-resolution cell imaging with Lattice SIM
and electron microscope imaging were used to observe mitochondria and lysosome in primary islet β and Min6 cells. Mitophagy Dye and mt-Keima were used to measure β cell mitophagy.
In
mice, we found that β cell survival and pancreatic β cell mass expansion as well as islet glucose induced insulin secretion in 2-week-old mice were reduced.
loss retarded postnatal β cell differentiation and growth as well as impaired mitochondria oxidative phosphorylation (OXPHOS) function to increase mitochondrial superoxide production, which might be attributed to impaired autophagy flux particularly mitochondria autophagy (mitophagy) induced by dysfunctional lysosome in
null β cells.
Our study revealed that NPC1 played an important role in maintaining normal lysosome function and mitochondria turnover, which ensured establishment of sufficient mitochondria OXPHOS for islet β cells differentiation and maturation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Competing Interests: The authors have declared that no competing interest exists. |
ISSN: | 1838-7640 1838-7640 |
DOI: | 10.7150/thno.90946 |