Tuesday 20 March 2018

Optimized Mitochondrial Targeting of Proteins Encoded by Modified mRNAs Rescues Cells Harboring Mutations in mtATP6

http://www.cell.com/cell-reports/abstract/S2211-1247(18)30253-5

Randall Marcelo Chin, Tadas Panavas, Jeffrey M. Brown, and Krista K. Johnson

  • Allotopic expression where a gene ordinarily encoded by mitochondrial DNA (mtDNA) is placed inside the nucleus, and modified such that the resultant protein is correctly transported into the mitochondria.
  • It is hoped that allotopic expression may be able to rescue pathologies which arise due to mutations in mitochondrial DNA: indeed, allotopic expression-based gene therapy is in phase 3 clinical trials for the mitochondrial disease LHON. 
  • mtDNA-encoded proteins are highly hydrophobic, causing them to often fold into import-incompetent states, thereby preventing them from entering the mitochondria. 
  • Mitochondrial targeting sequences (MTSs) and 3' untranslated regions (3' UTRs) have been used to target proteins or mRNA to the mitochondria. 
  • In this study, the authors performed a screen of 31MTSs and 15 UTRs in their ability to localize up to 9 allotopically expressed proteins to the mitochondrial DNA (note that mtDNA encodes 13 proteins, 22 tRNAs and 2 rRNAs).
  • Cybrid cells harbouring the 8993T>G point mutation in the mtATP6 gene were transiently transfected with a construct which was able to allotopically express mtATP6 and rescue the mtATP6-deficient cells.

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