bims-mitran 2023-07-16 papers

Issue of 2023–07–16
three papers selected by
Andreas Kohler, University of Graz

EMBO J. 2023 Jul 13. e113256

Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.

Nils Grotehans, Lynn McGarry, Hendrik Nolte, Vanessa Xavier, Moritz Kroker, Álvaro Jesús Narbona-Pérez, Soni Deshwal, Patrick Giavalisco, Thomas Langer, Thomas MacVicar.

Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.

Keywords: NME6; mitochondria; mitochondrial DNA; mitochondrial transcription; nucleotide metabolism

DOI: https://doi.org/10.15252/embj.2022113256

Nucleic Acids Res. 2023 Jul 13. pii: gkad591. [Epub ahead of print]

Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation.

Saori Ueda, Mikako Yagi, Ena Tomoda, Shinya Matsumoto, Yasushi Ueyanagi, Yura Do, Daiki Setoyama, Yuichi Matsushima, Asuteka Nagao, Tsutomu Suzuki, Tomomi Ide, Yusuke Mori, Noriko Oyama, Dongchon Kang, Takeshi Uchiumi.

The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.

DOI: https://doi.org/10.1093/nar/gkad591

Biochim Biophys Acta Mol Basis Dis. 2023 Jul 08. pii: S0925-4439(23)00170-9. [Epub ahead of print] 166804

Therapeutic potential of engineering the mitochondrial genome.

Mengmeng Liu, Wei Ji, Xin Zhao, Xiaoliang Liu, Ji-Fan Hu, Jiuwei Cui.

Mitochondrial diseases are a group of clinical disorders caused by mutations in the genes encoded by either the nuclear or the mitochondrial genome involved in mitochondrial oxidative phosphorylation. Disorders become evident when mitochondrial dysfunction reaches a cell-specific threshold. Similarly, the severity of disorders is related to the degree of gene mutation. Clinical treatments for mitochondrial diseases mainly rely on symptomatic management. Theoretically, replacing or repairing dysfunctional mitochondria to acquire and preserve normal physiological functions should be effective. Significant advances have been made in gene therapies, including mitochondrial replacement therapy, mitochondrial genome manipulation, nuclease programming, mitochondrial DNA editing, and mitochondrial RNA interference. In this paper, we review the recent progress in these technologies by focusing on advancements that overcome limitations.

Keywords: Embryonic stem cell; Mitochondrial disorders; Mitochondrial replacement therapy; Programmable nucleases; mtDNA editing; mtDNA mutation

DOI: https://doi.org/10.1016/j.bbadis.2023.166804