Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes

Lewis, Caitlin J.; Dixit, Bhavna; Batiuk, Elizabeth; Hall, Carter J.; O’Connor, Matthew S.; Boominathan, Amutha

doi:10.1016/j.redox.2020.101429

Cited by 13 publications

(11 citation statements)

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“…Another important factor is the impact of introducing such foreign genes into the nuclear environment and/or proteins into the cytosol, as altering gene sequences for optimal translation may also generate nucleotide and peptide sequences that can elicit host immune responses. Recent work in our lab revisited this theory [116,124], and while codon optimization does not address the challenges associated with mitochondrial targeting, import, or hydrophobicity of the encoded proteins, results indicate that optimizing the gene sequence for the expression system greatly enhances our ability to translate mitochondrial genes using the nuclear machinery. In every case, the codon-optimized constructs expressed discernible protein products that associated with mitochondria in vitro, unlike their recoded counterparts.…”

Section: Genetic and Molecular Characteristics Of Mtdna-encoded Prote...mentioning

confidence: 99%

“…Despite these and other efforts, constructs for many other subunits have hitherto failed to express at all, especially upon stable selection—that is, integration of the mitochondrial gene copy into the nuclear genome, rather than expression from a plasmid. As the mitochondrion is a remnant of an early endosymbiont, its highly conserved, retained genome bears similarity to those of prokaryotes and uses a coding sequence and codon usage frequencies that diverge from those of nuclear genes [ 124 ].…”

Section: Genetic and Molecular Characteristics Of Mtdna-encoded Prote...mentioning

confidence: 99%

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The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

et al. 2022

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Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome’s transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging.

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Section: Genetic and Molecular Characteristics Of Mtdna-encoded Prote...mentioning

confidence: 99%

Section: Genetic and Molecular Characteristics Of Mtdna-encoded Prote...mentioning

confidence: 99%

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

et al. 2022

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“…First, the mitochondrial encoded gene must be codon optimized for nuclear expression, as to accommodate for the differences in translation between the mitochondrial genome and nuclear genome. 125 Then, to deliver the now nuclear-expressed and cytoplasmic-translated mitochondrial encoded protein to mitochondria, a mitochondrial targeting sequence is fused to the gene. To deliver this modified mitochondrial gene, genetic payloads can be delivered by a viral vector or, in principle, be transfected directly to the cell as modified mRNA or protein.…”

Section: Allotopic Expressionmentioning

confidence: 99%

The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease

Kreymerman

Belle

et al. 2021

Trans. Vis. Sci. Tech.

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Mitochondrial dysfunction within the eye contributes to primarily mitochondrial diseases affecting the visual system such as Leber hereditary optic neuropathy (LHON) as well as more common ocular diseases, including glaucoma, diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration (AMD). For these reasons, druggable targets and gene therapies for improving mitochondrial function have been of significant interest within scientific and pharmaceutical endeavors seeking to improve visual outcomes in ocular disease. These therapies modulate mitochondrial functions, including mitochondrial membrane potential and membrane stability, redox signaling and oxidative stress, mitochondrial quality control including fusion/fission and biogenesis/mitophagy, apoptosis, and mitochondrial genetic-based therapies. As of now, several mitochondrial-targeted therapies have been approved in a limited number of countries, including photobiomodulation for AMD, idebenone for LHON, and SkQ1 for dry eye disease. Elamipretide for nonexudative AMD and gene therapy with GS010 for LHON have additionally shown encouraging results within clinical trials.Translational Relevance: Mitochondria are viable therapeutic targets for a broad spectrum of ocular diseases.

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“…The design of allotopically expressed mtDNA genes must adhere to different design standards: a mitochondrial targeting sequence is necessary so that the encoded protein is directed to the mitochondria. Additionally, differences in the codons used by the nuclear and mitochondrial genomes and differing codon preferences between the nuclear-cytosolic and mitochondrial translation systems must be considered [112]. mtDNA-encoded genes include 13 ETC complex subunits (for complex I, III, IV, and V), 22 mitochondria-specific tRNAs, and two mitochondrial rRNAs [24].…”

Section: Treatment Strategiesmentioning

confidence: 99%

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Prasuhn

Brüggemann

2021

Preprint

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Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

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Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes

Cited by 13 publications

References 92 publications

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics

The Present and Future of Mitochondrial-Based Therapeutics for Eye Disease

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

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