The constraints of allotopic expression

Nieto-Panqueva, Felipe; Rubalcava-Gracia, Diana; Hamel, Patrice P.; González-Halphen, Diego

doi:10.1016/j.mito.2023.09.004

Cited by 2 publications

(1 citation statement)

References 274 publications

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“…For the success of this approach, several challenges have been assessed and, in the last three decades, handled and improved. These include the different codon dictionaries and preferences between the mitochondrial and nuclear systems, the requirement of a mitochondrial targeting sequence (MTS) for translocation within the organelle, and the need for functional integration of the polypeptide into mitochondrial Complexes [174,175].…”

Section: Allotopic Expression Strategymentioning

confidence: 99%

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies

Del Dotto,

Musiani,

Baracca

et al. 2024

IJMS

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Mitochondrial ATP synthase (Complex V) catalyzes the last step of oxidative phosphorylation and provides most of the energy (ATP) required by human cells. The mitochondrial genes MT-ATP6 and MT-ATP8 encode two subunits of the multi-subunit Complex V. Since the discovery of the first MT-ATP6 variant in the year 1990 as the cause of Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome, a large and continuously increasing number of inborn variants in the MT-ATP6 and MT-ATP8 genes have been identified as pathogenic. Variants in these genes correlate with various clinical phenotypes, which include several neurodegenerative and multisystemic disorders. In the present review, we report the pathogenic variants in mitochondrial ATP synthase genes and highlight the molecular mechanisms underlying ATP synthase deficiency that promote biochemical dysfunctions. We discuss the possible structural changes induced by the most common variants found in patients by considering the recent cryo-electron microscopy structure of human ATP synthase. Finally, we provide the state-of-the-art of all therapeutic proposals reported in the literature, including drug interventions targeting mitochondrial dysfunctions, allotopic gene expression- and nuclease-based strategies, and discuss their potential translation into clinical trials.

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Section: Allotopic Expression Strategymentioning

confidence: 99%

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies

Del Dotto,

Musiani,

Baracca

et al. 2024

IJMS

View full text Add to dashboard Cite

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Identification of factors limiting the allotopic production of the Cox2 subunit of yeast cytochrome c oxidase

Nieto-Panqueva,

Vázquez-Acevedo,

Hamel

et al. 2024

Genetics

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Mitochondrial genes can be naturally or artificially relocalized in the nuclear genome in a process known as allotopic expression, such is the case of the mitochondrial cox2 gene, encoding subunit II of cytochrome c oxidase (CcO). In yeast, cox2 can be allotopically expressed and is able to restore respiratory growth of a cox2-null mutant if the Cox2 subunit carries the W56R substitution within the first transmembrane stretch. However, the COX2W56R strain exhibits reduced growth rates and lower steady-state CcO levels when compared to wild-type yeast. Here, we investigated the impact of overexpressing selected candidate genes predicted to enhance internalization of the allotopic Cox2W56R precursor into mitochondria. The overproduction of Cox20, Oxa1, and Pse1 facilitated Cox2W56R precursor internalization, improving the respiratory growth of the COX2W56R strain. Overproducing TIM22 components had a limited effect on Cox2W56R import, while overproducing TIM23-related components showed a negative effect. We further explored the role of the Mgr2 subunit within the TIM23 translocator in the import process by deleting and overexpressing the MGR2 gene. Our findings indicate that Mgr2 is instrumental in modulating the TIM23 translocon to correctly sort Cox2W56R. We propose a biogenesis pathway followed by the allotopically produced Cox2 subunit based on the participation of the two different structural/functional forms of the TIM23 translocon, TIM23MOTOR and TIM23SORT, that must follow a concerted and sequential mode of action to insert Cox2W56R into the inner mitochondrial membrane in the correct Nout-Cout topology.

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The constraints of allotopic expression

Cited by 2 publications

References 274 publications

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies

Identification of factors limiting the allotopic production of the Cox2 subunit of yeast cytochrome c oxidase

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