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Nuclear Expression of a Mitochondrial DNA Gene: Mitochondrial Targeting of Allotopically Expressed Mutant ATP6 in Transgenic Mice
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 < 0.05 ), 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.
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Experiments characterizing the phenotype of rescue mice gave mixed results and failed to definitively show an improvement in mice carrying the ATP6 mutation or to demonstrate robust expression of ATP6 in any of the tissues examined.
“However, the various experiments used to characterize the phenotype of the rescue mice gave mixed results and failed to definitively show an improvement in mice carrying the ATP6 mutation [117] or to demonstrate robust expression of ATP6 in any of the tissues examined.”
From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [117]
The Results and Discussion report mixed motor-test outcomes and no detectable differences in several mitochondrial-function measures, supporting the characterization of inconclusive results. But this paper studies mice engineered to express mutant or wild-type ATP6, not rescue mice carrying an existing ATP6 mutation; it therefore does not test whether such mice improved. It shows mitochondrial localization of expressed ATP6 in striatum but does not establish robust expression across the tissues examined. The supplied passages have no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDunn and Pinkert generated two versions of the nuclear-recoded mouse ATP6 gene: a wildtype and mt8993T > G that causes Leigh's syndrome and NARP in humans.
“Dunn and Pinkert generated two versions for the nuclear-recoded mouse ATP6 gene: a wildtype and mt8993T > G that causes Leigh’s syndrome and NARP in humans [117,167].”
From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [117]
Researchers have employed co-expression of mutant allotopic genes over WT versions in ND4 and ATP6 transgenic mice to recapitulate specific disease states such as LHON and NARP.
“Researchers have also employed co-expression of mutant allotopic genes over WT versions, as in the case of ND4 [151] and ATP6 transgenic mice [117,151], in attempts to recapitulate specific disease states, such as LHON and NARP.”
From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [117]
In previous studies, the allotopic ATP6 gene was randomly incorporated into the nuclear genome of C57BL/6 or B6(B6SJLF1) backgrounds.
“In these studies, the allotopic ATP6 gene was randomly incorporated into the nuclear genome of C57BL/6 or B6(B6SJLF1) backgrounds.24”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [24]
Previous approaches have predominantly used recombinant adenoviruses to target specific organs, such as the eye, expressing allotopic ND4, ATP6, or ND1 transgenes.
“Previous approaches have predominantly used recombinant adenoviruses to target specific organs, such as the eye, expressing allotopic ND4,23 ATP6,24 or ND150 transgenes.”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [24]
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Progress and prospects: gene therapy for mitochondrial DNA disease
Kyriakouli, D. S., Boesch, P., Taylor, R. W., & Lightowlers, R. N. (2008) · Gene Therapy · doi:10.1038/gt.2008.91 · Cited by 76
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Cwerman-Thibault, H., Augustin, S., Lechauve, C., Ayache, J., Ellouze, S., Sahel, J.-A., & Corral-Debrinski, M. (2015) · Molecular Therapy - Methods & Clinical Development · doi:10.1038/mtm.2015.3 · Cited by 86
The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics
Saravanan, S., Lewis, C. J., Dixit, B., O’Connor, M. S., Stolzing, A., & Boominathan, A. (2022) · Biomedicines · doi:10.3390/biomedicines10020490 · Cited by 13
Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo
Begelman, D. V., Dixit, B., Truong, C., King, C. D., Watson, M. A., Schilling, B., Brand, M. D., & Boominathan, A. (2024) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2024.101372 · Cited by 5
Metadata
- Authors
- Dunn, D. A., & Pinkert, C. A.
- Affiliations
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, 212 Samford Hall, Auburn, AL 36849, USA
- Venue
- Journal of Biomedicine and Biotechnology
- Publisher
- Wiley
- Published
- 2012
- Volume
- 2012
- Pages
- 1-7
- ISSN
- 1110-7243
- 1110-7251
- PMC
- PMC3388500
- Cited by
- 25
- References
- 1
- Language
- en
- Funders
- National Institutes of Health (HD053037, RR16286, EPS-0447675)
- MitoCure Foundation (HD053037, RR16286, EPS-0447675)
- National Science Foundation (HD053037, RR16286, EPS-0447675)
- Alabama Agricultural Experiment Station (HD053037, RR16286, EPS-0447675)
- Auburn University (HD053037, RR16286, EPS-0447675)
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