Small mitochondrial-targeted RNAs modulate endogenous mitochondrial protein expression in vivo

Neurobiol Dis. 2014 Sep:69:15-22. doi: 10.1016/j.nbd.2014.04.017. Epub 2014 May 5.

Abstract

Endogenous mitochondrial genes encode critical oxidative phosphorylation components and their mutation results in a set of disorders known collectively as mitochondrial encephalomyopathies. There is intensive interest in modulating mitochondrial function as organelle dysfunction has been associated with numerous disease states. Proteins encoded by the mitochondrial genome cannot be genetically manipulated by current techniques. Here we report the development of a mitochondrial-targeted RNA expression system (mtTRES) utilizing distinct non-coding leader sequences (NCLs) and enabling in vivo expression of small mitochondrial-targeted RNAs. mtTRES expressing small chimeric antisense RNAs was used as translational inhibitors (TLIs) to target endogenous mitochondrial protein expression in vivo. By utilizing chimeric antisense RNA we successfully modulate expression of two mitochondrially-encoded proteins, ATP6 and COXII, and demonstrate the utility of this system in vivo and in human cells. This technique has important and obvious research and clinical implications.

Keywords: Mitochondrial disorders; Mitochondrial encoded proteins; Non-coding small chimeric RNA; Translation inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / metabolism
  • Animals
  • Animals, Genetically Modified
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Gene Knockdown Techniques
  • Genetic Vectors
  • HeLa Cells
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Encephalomyopathies / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Protein Biosynthesis*
  • RNA Stability
  • RNA, Antisense / genetics*
  • RNA, Antisense / metabolism
  • RNA, Small Untranslated / genetics*
  • RNA, Small Untranslated / metabolism

Substances

  • Drosophila Proteins
  • Mitochondrial Proteins
  • RNA, Antisense
  • RNA, Small Untranslated
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Mitochondrial Proton-Translocating ATPases
  • mt:ATPase6 protein, Drosophila