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

Abstract EN

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<0.05), no locomotor differences (gait analysis; P<0.05) and enhanced endurance in Rota-Rod evaluations (P<0.05).

A6W mice exhibited inferior muscle strength (wire hang test; P<0.05), no difference in balance beam footsteps, accelerating Rota-Rod, pole test and gait analyses; (P<0.05) and superior performance in balance beam time-to-cross and constant velocity Rota-Rod analyses (P<0.05) 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>0.05).

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.