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DNA Delivery to Mitochondria: Sequence Specificity and Energy Enhancement

Lookup NU author(s): Dr Milana Koulintchenko, Professor Robert Lightowlers

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Abstract

Mitochondria are competent for DNA uptake in vitro, a mechanism which may support delivery of therapeutic DNA to complement organelle DNA mutations. We document here key aspects of the DNA import process, so as to further lay the ground for mitochondrial transfection in intact cells. We developed DNA import assays with isolated mitochondria from different organisms, using DNA substrates of various sequences and sizes. Further import experiments investigated the possible role of ATP and protein phosphorylation in the uptake process. The fate of adenine nucleotides and the formation of phosphorylated proteins were analyzed. We demonstrate that the efficiency of mitochondrial uptake depends on the sequence of the DNA to be translocated. The process becomes sequence-selective for large DNA substrates. Assays run with a natural mitochondrial plasmid identified sequence elements which promote organellar uptake. ATP enhances DNA import and allows tight integration of the exogenous DNA into mitochondrial nucleoids. ATP hydrolysis has to occur during the DNA uptake process and might trigger phosphorylation of co-factors. Our data contribute critical information to optimize DNA delivery into mitochondria and open the prospect of targeting whole mitochondrial genomes or complex constructs into mammalian organelles in vitro and in vivo.


Publication metadata

Author(s): Ibrahim N, Handa H, Cosset A, Koulintchenko M, Konstantinov Y, Lightowlers RN, Dietrich A, Weber-Lotfi F

Publication type: Article

Publication status: Published

Journal: Pharmaceutical Research

Year: 2011

Volume: 28

Issue: 11

Pages: 2871-2882

Print publication date: 12/07/2011

ISSN (print): 0724-8741

ISSN (electronic): 1573-904X

Publisher: Springer

URL: http://dx.doi.org/10.1007/s11095-011-0516-4

DOI: 10.1007/s11095-011-0516-4


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