Targeted transplantation of mitochondria to hepatocytes
Authors Gupta N, Wu CH, Wu GY
Received 10 July 2016
Accepted for publication 24 September 2016
Published 29 November 2016 Volume 2016:8 Pages 115—134
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Gerry Lake-Bakaar
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
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