What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes

Figueroa-Martínez, Francisco; Vázquez-Acevedo, Miriam; Cortés-Hernández, Paulina; García-Trejo, José J.; Davidson, Edgar; King, Michael P.; González‐Halphen, Diego

doi:10.1016/j.mito.2010.09.003

Cited by 43 publications

(31 citation statements)

References 44 publications

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“…It should be noted that, if natural import of mRNA into chloroplasts has been shown (36), natural mRNA import into mitochondria was never demonstrated. Moreover, allotropic expression of nucleusencoded mitochondrial genes can be unsuccessful due to incorrect localization of the protein into mitochondria (37,38). In these contexts, aUTR sequence offers a tool to target RNA and proteins to/into mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Differential targeting of VDAC3 mRNA isoforms influences mitochondria morphology

Michaud

Ubrig

Filleur

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular targeting of mRNAs has recently emerged as a prevalent mechanism to control protein localization. For mitochondria, a cotranslational model of protein import is now proposed in parallel to the conventional posttranslational model, and mitochondrial targeting of mRNAs has been demonstrated in various organisms. Voltage-dependent anion channels (VDACs) are the most abundant proteins in the outer mitochondrial membrane and the major transport pathway for numerous metabolites. Four nucleus-encoded VDACs have been identified in Arabidopsis thaliana. Alternative cleavage and polyadenylation generate two VDAC3 mRNA isoforms differing by their 3′ UTR. By using quantitative RT-PCR and in vivo mRNA visualization approaches, the two mRNA variants were shown differentially associated with mitochondria. The longest mRNA presents a 3′ extension named alternative UTR (aUTR) that is necessary and sufficient to target VDAC3 mRNA to the mitochondrial surface. Moreover, aUTR is sufficient for the mitochondrial targeting of a reporter transcript, and can be used as a tool to target an unrelated mRNA to the mitochondrial surface. Finally, VDAC3-aUTR mRNA variant impacts mitochondria morphology and size, demonstrating the role of mRNA targeting in mitochondria biogenesis.mRNA localization | mRNA sorting | green RNA | porin | plant E ukaryotic cells are characterized by compartmentalization of functions in complex organelles, and cell activity depends on synthesis and precise localization of proteins. The mechanisms of protein sorting are the subject of intense research, and models are often reevaluated (1). The earliest models for protein localization were based on the presence of targeting signals in the polypeptide sequences. However, the targeting of mRNAs to various subcellular regions has recently emerged as an essential regulatory step for protein localization (2).Mitochondria contain hundreds of proteins, but only a few are encoded by the mitochondrial genome. The other proteins are nucleus-encoded and imported into the organelle. Protein import into mitochondria is controlled by peptide sequences that are recognized by mitochondrial receptors (3, 4). In parallel with this posttranslational model, a cotranslational model is now emerging (2, 5). A microarray analysis in Saccharomyces cerevisiae has shown that approximately half of the mRNAs encoding mitochondrial proteins are found in the vicinity of mitochondria (6). Mitochondrial targeting of mRNA was also demonstrated in mammals and plants (7,8).Mechanisms of mitochondrial targeting of mRNAs were essentially studied in yeast. In this species, three factors have been clearly identified to influence mRNA targeting to the mitochondrial surface. (i) Targeting of many but not all mRNAs appears dependent on translation (9, 10). (ii) The RNA-binding protein Puf3p is essential for mitochondrial targeting of a subset of mRNAs (9). (iii) The translocase of the outer mitochondrial membrane (TOM complex) is also involved in mRNA binding (10-12). In addition, some mRNAs are...

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Section: Discussionmentioning

confidence: 99%

Differential targeting of VDAC3 mRNA isoforms influences mitochondria morphology

Michaud

Ubrig

Filleur

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, the nuclear-encoded atp6 of C. reinhardtii displays a large decrease in the hydrophobicity of the transmembrane region A, corresponding to the missing transmembrane domain in M. leidyi atp6, suggesting the absence of this domain may aid in the import of atp6 into the mitochondrion. The finding that atp6 is nuclear-encoded in M. leidyi makes it another potential model for the study of protein import to mitochondria, which is essential for mitochondrial gene therapy (Manfredi et al, 2002; Figueroa-Martinez et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Extreme mitochondrial evolution in the ctenophoreMnemiopsis leidyi: Insight from mtDNA and the nuclear genome

et al. 2011

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Recent advances in sequencing technology have led to a rapid accumulation of mitochondrial DNA (mtDNA) sequences, which now represent the wide spectrum of animal diversity. However, one animal phylum – Ctenophora – has, to date, remained completely unsampled. Ctenophores, a small group of marine animals, are of interest due to their unusual biology, controversial phylogenetic position, and devastating impact as an invasive species. Using data from the Mnemiopsis leidyi genome sequencing project, we PCR amplified and analyzed its complete mitochondrial (mt-) genome. At just over 10kb, the mt-genome of M. leidyi is the smallest animal mtDNA ever reported and is among the most derived. It has lost at least 25 genes, including atp6 and all tRNA genes. We show that atp6 has been relocated to the nuclear genome and has acquired introns and a mitochondrial targeting presequence, while tRNA genes have been genuinely lost, along with nuclear-encoded mt-aminoacyl tRNA synthetases. The mt-genome of M. leidyi also displays extremely high rates of sequence evolution, which likely led to the degeneration of both protein and rRNA genes. In particular, encoded rRNA molecules possess little similarity with their homologues in other organisms and have highly reduced secondary structures. At the same time, nuclear encoded mt-ribosomal proteins have undergone expansions, probably to compensate for the reductions in mt-rRNA. The unusual features identified in M. leidyi mtDNA make this organism an interesting system for the study of various aspects of mitochondrial biology, particularly protein and tRNA import and mt-ribosome structures, and add to its value as an emerging model species. Furthermore, the fast-evolving M. leidyi mtDNA should be a convenient molecular marker for species- and population-level studies.

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“…Exploration of these mechanisms holds promise for developing therapeutic strategies for human diseases caused by mitochondrial DNA mutations. There is no report thus far with strong functional and biochemical evidence that allotopically expressed proteins are properly incorporated into OXPHOS complexes in human cells [33], [34]. Our yeast-based approach has potential to unravel the general adaptations necessary for expressing mitochondrial proteins from nuclear DNA.…”

Section: Discussionmentioning

confidence: 99%

Experimental Relocation of the Mitochondrial ATP9 Gene to the Nucleus Reveals Forces Underlying Mitochondrial Genome Evolution

et al. 2012

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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. We demonstrate this approach on subunit 9/c of ATP synthase, successfully relocating this gene for the first time in any organism by expressing the ATP9 genes from Podospora anserina in Saccharomyces cerevisiae. This study substantiates the role of protein structure in mitochondrial gene transfer: expression of chimeric constructs reveals that the P. anserina proteins can be correctly imported into mitochondria due to reduced hydrophobicity of the first transmembrane segment. Nuclear expression of ATP9, while permitting almost fully functional oxidative phosphorylation, perturbs many cellular properties, including cellular morphology, and activates the heat shock response. Altogether, our study establishes a novel strategy for allotopic expression of mitochondrial genes, demonstrates the complex adaptations required to relocate ATP9, and indicates a reason that this gene was only transferred to the nucleus during the evolution of multicellular organisms.

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What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes

Cited by 43 publications

References 44 publications

Differential targeting of VDAC3 mRNA isoforms influences mitochondria morphology

Differential targeting of VDAC3 mRNA isoforms influences mitochondria morphology

Extreme mitochondrial evolution in the ctenophoreMnemiopsis leidyi: Insight from mtDNA and the nuclear genome

Experimental Relocation of the Mitochondrial ATP9 Gene to the Nucleus Reveals Forces Underlying Mitochondrial Genome Evolution

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