bims-mitran 2021-05-30 papers

Nucleic Acids Res. 2021 May 25. pii: gkab404. [Epub ahead of print]

YbeY is required for ribosome small subunit assembly and tRNA processing in human mitochondria.

Aaron R D'Souza, Lindsey Van Haute, Christopher A Powell, Christian D Mutti, Petra Páleníková, Pedro Rebelo-Guiomar, Joanna Rorbach, Michal Minczuk.

Mitochondria contain their own translation apparatus which enables them to produce the polypeptides encoded in their genome. The mitochondrially-encoded RNA components of the mitochondrial ribosome require various post-transcriptional processing steps. Additional protein factors are required to facilitate the biogenesis of the functional mitoribosome. We have characterized a mitochondrially-localized protein, YbeY, which interacts with the assembling mitoribosome through the small subunit. Loss of YbeY leads to a severe reduction in mitochondrial translation and a loss of cell viability, associated with less accurate mitochondrial tRNASer(AGY) processing from the primary transcript and a defect in the maturation of the mitoribosomal small subunit. Our results suggest that YbeY performs a dual, likely independent, function in mitochondria being involved in precursor RNA processing and mitoribosome biogenesis. Issue Section: Nucleic Acid Enzymes.

DOI: https://doi.org/10.1093/nar/gkab404

Nat Commun. 2021 May 28. 12(1): 3210

Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo.

Ugne Zekonyte, Sandra R Bacman, Jeff Smith, Wendy Shoop, Claudia V Pereira, Ginger Tomberlin, James Stewart, Derek Jantz, Carlos T Moraes.

Diseases caused by heteroplasmic mitochondrial DNA mutations have no effective treatment or cure. In recent years, DNA editing enzymes were tested as tools to eliminate mutant mtDNA in heteroplasmic cells and tissues. Mitochondrial-targeted restriction endonucleases, ZFNs, and TALENs have been successful in shifting mtDNA heteroplasmy, but they all have drawbacks as gene therapy reagents, including: large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness. Here we report the adaptation of a gene editing platform based on the I-CreI meganuclease known as ARCUS®. These mitochondrial-targeted meganucleases (mitoARCUS) have a relatively small size, are monomeric, and can recognize sequences differing by as little as one base pair. We show the development of a mitoARCUS specific for the mouse m.5024C>T mutation in the mt-tRNAAla gene and its delivery to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNAAla levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.

DOI: https://doi.org/10.1038/s41467-021-23561-7

Sci Rep. 2021 May 25. 11(1): 10897

Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment.

Hideki Maeda, Daisuke Kami, Ryotaro Maeda, Akira Shikuma, Satoshi Gojo.

Mitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

DOI: https://doi.org/10.1038/s41598-021-90316-1

Nat Rev Genet. 2021 May 24.

Biparental inheritance of mitochondrial DNA revisited.

Alistair T Pagnamenta, Wei Wei, Shamima Rahman, Patrick F Chinnery.

DOI: https://doi.org/10.1038/s41576-021-00380-6

Sci Adv. 2021 May;pii: eabf5374. [Epub ahead of print]7(22):

BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.

The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation-dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.

DOI: https://doi.org/10.1126/sciadv.abf5374