Mitochondrial proteins constructs and uses thereof

Abstract

Disclosed are novel fusion protein constructs comprising a functional mitochondrial protein, that can enter mitochondria within intact cells. Further disclosed are methods of treating mitochondrial disorders by the disclosed fusion proteins and compositions therefor.

1 . A fusion protein comprising an HIV-1 transactivator of transcription (TAT) domain fused to a human pyruvate dehydrogenase E1 component alpha subunit (PDHE1a) and a human mitochondria targeting sequence (MTS), wherein the MTS is situated between the TAT domain and the PDHE1a, the PDHE1a is C-terminal to the MTS, and the MTS is heterologous to the PDHE1a. 
     
     
         2 . The fusion protein of  claim 1 , wherein the MTS is a human citrate synthase (CS) MTS. 
     
     
         3 . The fusion protein of  claim 2 , wherein the MTS comprises the amino acid sequence of SEQ ID NO. 23. 
     
     
         4 . The fusion protein of  claim 1 , further comprising a linker covalently linking the TAT domain to the MTS. 
     
     
         5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein according to  claim 1  as an active ingredient. 
     
     
         6 . A method for introducing a human pyruvate dehydrogenase E1 component alpha subunit (PDHE1a) into a subject, comprising administering to the subject the fusion protein of  claim 1 . 
     
     
         7 . A method for treating or alleviating a mitochondrial disorder, comprising administering to a human subject in need thereof the fusion protein of  claim 1 . 
     
     
         8 . The method of  claim 7 , wherein the fusion protein is intravenously administered to the subject.