Therapeutic applications of the TAT-mediated protein transduction system for complex I deficiency and other mitochondrial diseases

Ann N Y Acad Sci. 2015 Sep;1350:17-28. doi: 10.1111/nyas.12858. Epub 2015 Aug 14.


Among the five enzyme complexes in the oxidative phosphorylation system, NADH-coenzyme Q oxidoreductase (also called complex I) is the largest, most intricate, and least understood. This enzyme complex spans the inner mitochondrial membrane and catalyzes the first step of electron transfer by the oxidation of NADH, and thereby provides two electrons for the reduction of quinone to quinol. Complex I deficiency is associated with many severe mitochondrial diseases, including Leber hereditary optic neuropathy and Leigh syndrome. However, to date, conventional treatments for the majority of genetic mitochondrial diseases are only palliative. Developing a reliable and convenient therapeutic approach is therefore considered to be an urgent need. Targeted proteins fused with the protein transduction domain of human immunodeficiency virus 1 transactivator of transcription (TAT) have been shown to enter cells by crossing plasma membranes while retaining their biological activities. Recent developments show that, in fusion with mitochondrial targeting sequences (MTSs), TAT-MTS-bound cargo can be correctly transported into mitochondria and restore the missing function of the cargo protein in patients' cells. The available evidence suggests that the TAT-mediated protein transduction system holds great promise as a potential therapeutic approach to treat complex I deficiency, as well as other mitochondrial diseases.

Keywords: complex I; enzyme replacement therapy; mitochondria; oxidative phosphorylation; protein transduction domain; transactivator of transcription peptide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA, Mitochondrial / metabolism*
  • DNA, Mitochondrial / therapeutic use
  • DNA, Recombinant / metabolism
  • DNA, Recombinant / therapeutic use
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism*
  • Electron Transport Complex I / therapeutic use
  • Enzyme Replacement Therapy / methods
  • HIV-1 / metabolism
  • Humans
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Models, Biological*
  • Oxidative Phosphorylation
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Sorting Signals*
  • Protein Transport
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction*
  • Targeted Gene Repair / methods
  • tat Gene Products, Human Immunodeficiency Virus / chemistry
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • DNA, Mitochondrial
  • DNA, Recombinant
  • Peptide Fragments
  • Protein Sorting Signals
  • Recombinant Fusion Proteins
  • tat Gene Products, Human Immunodeficiency Virus
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency