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Journal of Biomedicine and Biotechnology
Volume 2012 (2012), Article ID 541245, 7 pages
http://dx.doi.org/10.1155/2012/541245
Research Article

Nuclear Expression of a Mitochondrial DNA Gene: Mitochondrial Targeting of Allotopically Expressed Mutant ATP6 in Transgenic Mice

Department of Pathobiology, College of Veterinary Medicine, Auburn University, 212 Samford Hall, Auburn, AL 36849, USA

Received 10 January 2012; Revised 13 April 2012; Accepted 16 April 2012

Academic Editor: Oreste Gualillo

Copyright © 2012 David A. Dunn and Carl A. Pinkert. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Nuclear encoding of mitochondrial DNA transgenes followed by mitochondrial targeting of the expressed proteins (allotopic expression; AE) represents a potentially powerful strategy for creating animal models of mtDNA disease. Mice were created that allotopically express either a mutant (A6M) or wildtype (A6W) mt-Atp6 transgene. Compared to non-transgenic controls, A6M mice displayed neuromuscular and motor deficiencies (wire hang, pole, and balance beam analyses; 𝑃 < 0 . 0 5 ), no locomotor differences (gait analysis; 𝑃 < 0 . 0 5 ) and enhanced endurance in Rota-Rod evaluations ( 𝑃 < 0 . 0 5 ). A6W mice exhibited inferior muscle strength (wire hang test; 𝑃 < 0 . 0 5 ), no difference in balance beam footsteps, accelerating Rota-Rod, pole test and gait analyses; ( 𝑃 < 0 . 0 5 ) and superior performance in balance beam time-to-cross and constant velocity Rota-Rod analyses ( 𝑃 < 0 . 0 5 ) in comparison to non-transgenic control mice. Mice of both transgenic lines did not differ from non-transgenic controls in a number of bioenergetic and biochemical tests including measurements of serum lactate and mitochondrial MnSOD protein levels, ATP synthesis rate, and oxygen consumption ( 𝑃 > 0 . 0 5 ). This study illustrates a mouse model capable of circumventing in vivo mitochondrial mutations. Moreover, it provides evidence supporting AE as a tool for mtDNA disease research with implications in development of DNA-based therapeutics.