Targeted transplantation of mitochondria to hepatocytes
Nidhi Gupta, Catherine H Wu, George Y Wu Department of Medicine, Division of Gastroenterology–Hepatology, University of Connecticut Health Center, Farmington, CT, USA Background: Mitochondrial defects in hepatocytes can result in liver dysfunction and death. Hepatocytes have cell-surface a...
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Dove Medical Press
2016
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oai:doaj.org-article:ade4d9673b9d423fbf63bb39883019ee2021-12-02T07:09:06ZTargeted transplantation of mitochondria to hepatocytes1179-1535https://doaj.org/article/ade4d9673b9d423fbf63bb39883019ee2016-11-01T00:00:00Zhttps://www.dovepress.com/targeted-transplantation-of-mitochondria-to-hepatocytes-peer-reviewed-article-HMERhttps://doaj.org/toc/1179-1535Nidhi Gupta, Catherine H Wu, George Y Wu Department of Medicine, Division of Gastroenterology–Hepatology, University of Connecticut Health Center, Farmington, CT, USA Background: Mitochondrial defects in hepatocytes can result in liver dysfunction and death. Hepatocytes have cell-surface asialoglycoprotein receptors (AsGRs) which internalize AsGs within endosomes. The aim of this study was to determine whether mitochondria could be targeted to hepatocytes by AsGR-mediated endocytosis. Materials and methods: An AsG, AsOR, was linked to polylysine to create a conjugate, AsOR-PL, and complexed with healthy and functional mitochondria (defined by normal morphology, cytochrome c assays, and oxygen-consumption rates). Huh7 (AsGR+) and SK Hep1 (AsGR–) cells were treated with a mitochondrial toxin to form Huh7-Mito– and SK Hep1-Mito– cells, lacking detectable mitochondrial DNA. An endosomolytic peptide, LLO, was coupled to AsOR to form AsOR-LLO. A lysosomal inhibitor, amantadine, was used in mitochondria-uptake studies as a control for nonspecific endosomal release. Results: Coincubation of complexed mitochondria and AsOR-LLO with Huh7-Mito– cells increased mitochondrial DNA to >9,700-fold over control at 7 days (P<0.001), and increased mitochondrial oxygen-consumption rates to >90% of control by 10 days. Conclusion: Rescue of mitochondria-damaged hepatocytes can be achieved by targeted uptake of normal mitochondria through receptor-mediated endocytosis. Keywords: mitochondrial toxicity, mitochondria–protein complex, receptor-mediated uptake, endosomal escape, targeted deliveryGupta NWu CHWu GYDove Medical PressarticleMitochondrial toxicitymitochondria-protein complexreceptor-mediated uptakeendosomal escapetargeted delivery.Diseases of the digestive system. GastroenterologyRC799-869ENHepatic Medicine: Evidence and Research, Vol Volume 8, Pp 115-134 (2016) |
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DOAJ |
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DOAJ |
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EN |
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Mitochondrial toxicity mitochondria-protein complex receptor-mediated uptake endosomal escape targeted delivery. Diseases of the digestive system. Gastroenterology RC799-869 |
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Mitochondrial toxicity mitochondria-protein complex receptor-mediated uptake endosomal escape targeted delivery. Diseases of the digestive system. Gastroenterology RC799-869 Gupta N Wu CH Wu GY Targeted transplantation of mitochondria to hepatocytes |
| description |
Nidhi Gupta, Catherine H Wu, George Y Wu Department of Medicine, Division of Gastroenterology–Hepatology, University of Connecticut Health Center, Farmington, CT, USA Background: Mitochondrial defects in hepatocytes can result in liver dysfunction and death. Hepatocytes have cell-surface asialoglycoprotein receptors (AsGRs) which internalize AsGs within endosomes. The aim of this study was to determine whether mitochondria could be targeted to hepatocytes by AsGR-mediated endocytosis. Materials and methods: An AsG, AsOR, was linked to polylysine to create a conjugate, AsOR-PL, and complexed with healthy and functional mitochondria (defined by normal morphology, cytochrome c assays, and oxygen-consumption rates). Huh7 (AsGR+) and SK Hep1 (AsGR–) cells were treated with a mitochondrial toxin to form Huh7-Mito– and SK Hep1-Mito– cells, lacking detectable mitochondrial DNA. An endosomolytic peptide, LLO, was coupled to AsOR to form AsOR-LLO. A lysosomal inhibitor, amantadine, was used in mitochondria-uptake studies as a control for nonspecific endosomal release. Results: Coincubation of complexed mitochondria and AsOR-LLO with Huh7-Mito– cells increased mitochondrial DNA to >9,700-fold over control at 7 days (P<0.001), and increased mitochondrial oxygen-consumption rates to >90% of control by 10 days. Conclusion: Rescue of mitochondria-damaged hepatocytes can be achieved by targeted uptake of normal mitochondria through receptor-mediated endocytosis. Keywords: mitochondrial toxicity, mitochondria–protein complex, receptor-mediated uptake, endosomal escape, targeted delivery |
| format |
article |
| author |
Gupta N Wu CH Wu GY |
| author_facet |
Gupta N Wu CH Wu GY |
| author_sort |
Gupta N |
| title |
Targeted transplantation of mitochondria to hepatocytes |
| title_short |
Targeted transplantation of mitochondria to hepatocytes |
| title_full |
Targeted transplantation of mitochondria to hepatocytes |
| title_fullStr |
Targeted transplantation of mitochondria to hepatocytes |
| title_full_unstemmed |
Targeted transplantation of mitochondria to hepatocytes |
| title_sort |
targeted transplantation of mitochondria to hepatocytes |
| publisher |
Dove Medical Press |
| publishDate |
2016 |
| url |
https://doaj.org/article/ade4d9673b9d423fbf63bb39883019ee |
| work_keys_str_mv |
AT guptan targetedtransplantationofmitochondriatohepatocytes AT wuch targetedtransplantationofmitochondriatohepatocytes AT wugy targetedtransplantationofmitochondriatohepatocytes |
| _version_ |
1718399594917789696 |