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Allotopic expression

Randall Marcelo Chin, Tadas Panavas, Jeffrey M Brown, Krista K Johnson
Mitochondrial disease may be caused by mutations in the protein-coding genes of the mitochondrial genome. A promising strategy for treating such diseases is allotopic expression-the translation of wild-type copies of these proteins in the cytosol, with subsequent translocation into the mitochondria, resulting in rescue of mitochondrial function. In this paper, we develop an automated, quantitative, and unbiased screening platform to evaluate protein localization and mitochondrial morphology. This platform was used to compare 31 mitochondrial targeting sequences and 15 3' UTRs in their ability to localize up to 9 allotopically expressed proteins to the mitochondria and their subsequent impact on mitochondrial morphology...
March 13, 2018: Cell Reports
Luisa Iommarini, Anna Ghelli, Concetta Valentina Tropeano, Ivana Kurelac, Giulia Leone, Sara Vidoni, Anne Lombes, Massimo Zeviani, Giuseppe Gasparre, Anna Maria Porcelli
Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH-ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms. A critical role of human ND1 both in CI biogenesis and in the dynamic organization of supercomplexes has been depicted, although the proof of concept is still missing and the critical amount of ND1 protein necessary for a proper assembly of both CI and supercomplexes is not defined...
March 7, 2018: International Journal of Molecular Sciences
Mario H Barros, Alexander Tzagoloff
Translation of mitochondrial gene products in Saccharomyces cerevisiae depends on mRNA-specific activators that bind to the 5' untranslated regions and promote translation on mitochondrial ribosomes. Here we find that Aep3p, previously shown to stabilize the bicistronic ATP8-ATP6 mRNA and facilitate initiation of translation from unformylated methionine, also activates specifically translation of ATP8 This is supported by several lines of evidence. Temperature-sensitive aep3 mutants are selectively blocked in incorporating [(35)S]methionine into Atp8p at nonpermissive but not at the permissive temperature...
June 1, 2017: Molecular Biology of the Cell
Amutha Boominathan, Shon Vanhoozer, Nathan Basisty, Kathleen Powers, Alexandra L Crampton, Xiaobin Wang, Natalie Friedricks, Birgit Schilling, Martin D Brand, Matthew S O'Connor
We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation...
November 2, 2016: Nucleic Acids Research
Jason H Peragallo, Nancy J Newman
PURPOSE OF REVIEW: To discuss recent advances in potential treatments for Leber hereditary optic neuropathy (LHON), a typically visually devastating hereditary optic neuropathy caused by mutations in the mitochondrial genome. RECENT FINDINGS: Idebenone has been proposed as a means of bypassing defective complex I activity and a free radical scavenger to prevent oxidative damage. EPI-743 may have more potency than idebenone, but no clinical trials have been performed...
November 2015: Current Opinion in Ophthalmology
A-Mei Zhang, Qiu-Xiang Hu, Feng-Liang Liu, Rui Bi, Bi-Qing Yang, Wen Zhang, Hao Guo, Ian Logan, Yong-Tang Zheng, Yong-Gang Yao
Drug addiction is one of the most serious social problems in the world today and addicts are always at a high risk of acquiring HIV infection. Mitochondrial impairment has been reported in both drug addicts and in HIV patients undergoing treatment. In this study, we aimed to investigate whether mitochondrial DNA (mtDNA) haplogroup could affect the risk of drug addiction and HIV-1 infection in Chinese. We analyzed mtDNA sequence variations of 577 Chinese intravenous drug addicts (289 with HIV-1 infection and 288 without) and compared with 2 control populations (n = 362 and n = 850)...
August 2016: Molecular Neurobiology
Hélène Cwerman-Thibault, Sébastien Augustin, Christophe Lechauve, Jessica Ayache, Sami Ellouze, José-Alain Sahel, Marisol Corral-Debrinski
Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein...
2015: Molecular Therapy. Methods & Clinical Development
Ana Leitão-Rocha, Pedro Guedes-Dias, Brígida R Pinho, Jorge M A Oliveira
Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and age-dependent mitochondrial damage, have all been connected with neurological disorders. These include not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease...
2015: Current Medicinal Chemistry
David A Dunn, Carl A Pinkert
Progress in animal modeling of polymorphisms and mutations in mitochondrial DNA (mtDNA) is not as developed as nuclear transgenesis due to a host of cellular and physiological distinctions. mtDNA mutation modeling is of critical importance as mutations in the mitochondrial genome give rise to a variety of pathological conditions and play a contributing role in many others. Nuclear localization and transcription of mtDNA genes followed by cytoplasmic translation and transport into mitochondria (allotopic expression, AE) provide an opportunity to create in vivo modeling of a targeted mutation in mitochondrial genes and has been suggested as a strategy for gene replacement therapy in patients harboring mitochondrial DNA mutations...
2015: Methods in Molecular Biology
Rajeshwari Koilkonda, Hong Yu, Venu Talla, Vittorio Porciatti, William J Feuer, William W Hauswirth, Vince Chiodo, Kirsten E Erger, Sanford L Boye, Alfred S Lewin, Thomas J Conlon, Lauren Renner, Martha Neuringer, Carol Detrisac, John Guy
PURPOSE: To demonstrate safety and efficacy of allotopic human ND4 for treatment of a Leber's hereditary optic neuropathy (LHON) mouse model harboring the G11778A mitochondrial mutation. METHODS: We induced LHON in mice by intravitreal injection of mutant (G11778A) human ND4 DNA, responsible for most cases of LHON, that was directed to mitochondria using an AAV2 vector to which we appended a mitochondrial targeting sequence to the VP2 capsid. We then attempted rescue of visual loss using our test article (ScAAV2-P1ND4v2) containing a synthetic nuclear encoded G11778G ND4 gene that was allotopically expressed...
October 23, 2014: Investigative Ophthalmology & Visual Science
Salar Torabi, Pavan Umate, Nikolay Manavski, Magdalena Plöchinger, Laura Kleinknecht, Hanumakumar Bogireddi, Reinhold G Herrmann, Gerhard Wanner, Wolfgang P Schröder, Jörg Meurer
The chloroplast-encoded low molecular weight protein PsbN is annotated as a photosystem II (PSII) subunit. To elucidate the localization and function of PsbN, encoded on the opposite strand to the psbB gene cluster, we raised antibodies and inserted a resistance cassette into PsbN in both directions. Both homoplastomic tobacco (Nicotiana tabacum) mutants psbN-F and psbN-R show essentially the same PSII deficiencies. The mutants are extremely light sensitive and failed to recover from photoinhibition. Although synthesis of PSII proteins was not altered significantly, both mutants accumulated only ∼25% of PSII proteins compared with the wild type...
March 2014: Plant Cell
Byron L Lam, William J Feuer, Joyce C Schiffman, Vittorio Porciatti, Ruth Vandenbroucke, Potyra R Rosa, Giovanni Gregori, John Guy
IMPORTANCE Establishing the natural history of G11778A Leber hereditary optic neuropathy (LHON) is important to determine the optimal end points to assess the safety and efficacy of a planned gene therapy trial. OBJECTIVE To use the results of the present natural history study of patients with G11778A LHON to plan a gene therapy clinical trial that will use allotopic expression by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous...
April 1, 2014: JAMA Ophthalmology
Rajeshwari D Koilkonda, Hong Yu, Tsung-Han Chou, William J Feuer, Marco Ruggeri, Vittorio Porciatti, David Tse, William W Hauswirth, Vince Chiodo, Sanford L Boye, Alfred S Lewin, Martha Neuringer, Lauren Renner, John Guy
IMPORTANCE We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression)...
April 1, 2014: JAMA Ophthalmology
Claudia Calabrese, Luisa Iommarini, Ivana Kurelac, Maria Antonietta Calvaruso, Mariantonietta Capristo, Pier-Luigi Lollini, Patrizia Nanni, Christian Bergamini, Giordano Nicoletti, Carla De Giovanni, Anna Ghelli, Valentina Giorgio, Mariano Francesco Caratozzolo, Flaviana Marzano, Caterina Manzari, Christine M Betts, Valerio Carelli, Claudio Ceccarelli, Marcella Attimonelli, Giovanni Romeo, Romana Fato, Michela Rugolo, Apollonia Tullo, Giuseppe Gasparre, Anna Maria Porcelli
BACKGROUND: Aerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift. This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. In this framework, the role of mitochondrial complex I is still debated, in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism...
2013: Cancer & Metabolism
M Kanabus, S J Heales, S Rahman
Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results...
April 2014: British Journal of Pharmacology
Valentín Cruz-Torres, Miriam Vázquez-Acevedo, Rodolfo García-Villegas, Xochitl Pérez-Martínez, Guillermo Mendoza-Hernández, Diego González-Halphen
Deletion of the yeast mitochondrial gene COX2 encoding subunit 2 (Cox2) of cytochrome c oxidase (CcO) results in loss of respiration (Δcox2 strain). Supekova et al. (2010) [1] transformed a Δcox2 strain with a vector expressing Cox2 with a mitochondrial targeting sequence (MTS) and the point mutation W56R (Cox2(W56R)), restoring respiratory growth. Here, the CcO carrying the allotopically-expressed Cox2(W56R) was characterized. Yeast mitochondria from the wild-type (WT) and the Δcox2+Cox2(W56R) strains were subjected to Blue Native electrophoresis...
December 2012: Biochimica et Biophysica Acta
Maïlis Bietenhader, Alexandre Martos, Emmanuel Tetaud, Raeka S Aiyar, Carole H Sellem, Roza Kucharczyk, Sandra Clauder-Münster, Marie-France Giraud, François Godard, Bénédicte Salin, Isabelle Sagot, Julien Gagneur, Michelle Déquard-Chablat, Véronique Contamine, Sylvie Hermann-Le Denmat, Annie Sainsard-Chanet, Lars M Steinmetz, Jean-Paul di Rago
Only a few genes remain in the mitochondrial genome retained by every eukaryotic organism that carry out essential functions and are implicated in severe diseases. Experimentally relocating these few genes to the nucleus therefore has both therapeutic and evolutionary implications. Numerous unproductive attempts have been made to do so, with a total of only 5 successes across all organisms. We have taken a novel approach to relocating mitochondrial genes that utilizes naturally nuclear versions from other organisms...
2012: PLoS Genetics
David A Dunn, Carl A Pinkert
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...
2012: Journal of Biomedicine & Biotechnology
David A Dunn, Matthew V Cannon, Michael H Irwin, Carl A Pinkert
BACKGROUND: Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic states in human patients. Development of animal models harboring mtDNA mutations is crucial to elucidating pathways of disease and as models for preclinical assessment of therapeutic interventions. SCOPE OF REVIEW: This review covers the knowledge gained through animal models of mtDNA mutations and the strategies used to produce them. Animals derived from spontaneous mtDNA mutations, somatic cell nuclear transfer (SCNT), nuclear translocation of mitochondrial genes followed by mitochondrial protein targeting (allotopic expression), mutations in mitochondrial DNA polymerase gamma, direct microinjection of exogenous mitochondria, and cytoplasmic hybrid (cybrid) embryonic stem cells (ES cells) containing exogenous mitochondria (transmitochondrial cells) are considered...
May 2012: Biochimica et Biophysica Acta
Mario H Barros, Malgorzata Rak, Janaina A Paulela, Alexander Tzagoloff
The bacterial GatCAB operon for tRNA-dependent amidotransferase (AdT) catalyzes the transamidation of mischarged glutamyl-tRNA(Gln) to glutaminyl-tRNA(Gln). Here we describe the phenotype of temperature-sensitive (ts) mutants of GTF1, a gene proposed to code for subunit F of mitochondrial AdT in Saccharomyces cerevisiae. The ts gtf1 mutants accumulate an electrophoretic variant of the mitochondrially encoded Cox2p subunit of cytochrome oxidase and an unstable form of the Atp8p subunit of the F(1)-F(0) ATP synthase that is degraded, thereby preventing assembly of the F(0) sector...
September 23, 2011: Journal of Biological Chemistry
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