title: Targeted transplantation of mitochondria to hepatocytes.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Rescue of mitochondria-damaged hepatocytes can be achieved by targeted uptake of normal mitochondria through receptor-mediated endocytosis.
authors.affiliation: Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: George Y
authors.initials: GY
authors.lastname: Wu
keywords: endosomal escape; mitochondrial toxicity; mitochondria–protein complex; receptor-mediated uptake; targeted delivery