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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
DOI https://doi.org/10.2147/HMER.S116852
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Akshita Wason
Peer reviewer comments 3
Editor who approved publication: Dr Gerry Lake-Bakaar
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