bims-mitran 2023-12-03 papers

Issue of 2023–12–03
nine papers selected by
Andreas Kohler, Umeå University

Trends Plant Sci. 2023 Nov 27. pii: S1360-1385(23)00370-9. [Epub ahead of print]

Uncovering the mechanism of mitochondrial translation initiation in plants.

Mitochondrial translation differs significantly from that conducted in bacteria and plastids. Recent research conducted by Tran and colleagues has unveiled the plant-specific mechanisms of mitochondrial translation initiation. The authors identified two Arabidopsis thaliana (arabidopsis) mTRAN proteins that may bind to the 5' untranslated region (UTR) of mitochondrial mRNAs by recognising newly discovered A/U-rich motifs.

Keywords: mitochondria; mitoribosome; ribosome; translation

DOI: https://doi.org/10.1016/j.tplants.2023.11.011

Nat Metab. 2023 Nov 30.

Efficient elimination of MELAS-associated m.3243G mutant mitochondrial DNA by an engineered mitoARCUS nuclease.

Wendy K Shoop, Janel Lape, Megan Trum, Alea Powell, Emma Sevigny, Adam Mischler, Sandra R Bacman, Flavia Fontanesi, Jeff Smith, Derek Jantz, Cassandra L Gorsuch, Carlos T Moraes.

Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.

DOI: https://doi.org/10.1038/s42255-023-00932-6

Nature. 2023 Nov 29.

Atomic-level structures show how accuracy is maintained in protein synthesis.

Keywords: Biochemistry; Microscopy; Structural biology

DOI: https://doi.org/10.1038/d41586-023-03382-y

Sci Rep. 2023 Nov 29. 13(1): 21016

Mitochondrial DNA copy number is associated with Crohn's disease: a comprehensive Mendelian randomization analysis.

Xianlei Cai, Xueying Li, Chao Liang, Miaozun Zhang, Yuan Xu, Zhebin Dong, Yihui Weng, Weiming Yu.

Mitochondrial DNA plays a critical role in the pathophysiological process of inflammation. However, the relationship between mitochondrial DNA copy number (mtDNA-CN) and inflammatory bowel diseases (IBD) remains poorly understood. We conducted a comprehensive Mendelian randomization (MR) using three instrumental variables (IVs) to explore the causal associations between mtDNA-CN and IBD, including Crohn's disease (CD), ulcerative colitis (UC). MR-Egger regression, weighted median, inverse-variance weighted (IVW), and weighted mode methods were used to evaluate the potential causal associations. The robustness of the IVW estimates was determined using the leave-one-out sensitivity test. A meta-analysis was conducted to pool the results from the three sets of IVs. Upon analysis, the findings of the current study revealed that genetically predicted mtDNA-CN was not associated with IBD (CD + UC) and UC. The results of MR analyses between mtDNA-CN and CD risk were inconsistent by using three sets of IVs. After a meta-analysis, we found that genetically predicted mtDNA-CN was associated with CD risk (odds ratio = 2.09; 95% confidence interval: 1.37-3.18). This finding was also confirmed by multivariable MR analyses and remained robust when tested with the leave-one-out sensitivity test. In conclusion, genetically predicted mtDNA-CN was found to be associated with CD risk. Therefore, mtDNA levels in the blood could potentially be used as a marker for CD risk assessment. Further studies are needed to elucidate the underlying mechanisms and validate the results of this study.

DOI: https://doi.org/10.1038/s41598-023-48175-5

Trends Genet. 2023 Nov 29. pii: S0168-9525(23)00257-3. [Epub ahead of print]

TFAM mislocalization during spermatogenesis.

Sam Kavoosi, Martin Picard, Brett A Kaufman.

Mitochondrial DNA (mtDNA) is inherited almost exclusively from the maternal lineage. Paternal destruction of either mtDNA or whole mitochondria has been the dominant model for mtDNA transmission. Recently, Lee et al. provided evidence for mitochondrial transcription factor A (TFAM) import sequence regulation as a potential cause for mtDNA depletion in human sperm before fertilization.

Keywords: TFAM; mtDNA; spermatogenesis; uniparental inheritance

DOI: https://doi.org/10.1016/j.tig.2023.11.002

Eur J Med Genet. 2023 Nov 27. pii: S1769-7212(23)00195-7. [Epub ahead of print] 104889

New description of an MRPS2 homozygous patient: Further features to help expend the phenotype.

Thalia Papadopoulos, Pauline Gaignard, Manuel Schiff, Marlène Rio, Daniela Karall, Adrien Legendre, Alain Verloes, Lyse Ruaud.

Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects, two with sensorineural hearing impairment, mild developmental delay, hypoglycemia, lactic acidemia and combined oxidative phosphorylation system deficiency and another, recently, presenting with a less severe phenotype. In order to expand the phenotype, we describe a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features.

Keywords: Autistic features; Joint hypermobility; Mito-ribosomal protein S2; Mitochondrial ribosomes; OXPHOS complex deficiencies

DOI: https://doi.org/10.1016/j.ejmg.2023.104889

Mitochondrion. 2023 Nov 29. pii: S1567-7249(23)00094-6. [Epub ahead of print]

Assessment of mitochondrial DNA copy number variation relative to nuclear DNA quantity between different tissues.

Jana Naue, Catarina Xavier, Steffen Hörer, Walther Parson, Sabine Lutz-Bonengel.

Mitochondrial DNA is a widely tested genetic marker in various fields of research and diagnostics. Nonetheless, there is still little understanding on its abundance and quality within different tissues. Aiming to obtain deeper knowledge about the content and quality of mtDNA, we investigated nine tissues including blood, bone, brain, hair (root and shaft), cardiac muscle, liver, lung, skeletal muscle, and buccal mucosa of 32 deceased individuals using two real-time quantitative PCR-based assays with differently sized mtDNA and nDNA targets. The results revealed that the quantity of nDNA is a weak surrogate to estimate mtDNA quantities among tissues of an individual, as well as tissues across individuals. Especially hair showed extreme variation, depicting a range of multiple magnitudes of mtDNA molecules per hair fragment. Furthermore, degradation can lead to fewer fragments being available for PCR. The results call for parallel determination of the quantity and quality of mtDNA prior to downstream genotyping assays.

Keywords: DNA degradation; Mitochondrial DNA; Real-time quantitative PCR; forensic DNA analysis; human tissues; quantification

DOI: https://doi.org/10.1016/j.mito.2023.11.006

Cell Biochem Funct. 2023 Nov 28.

Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.

Behnaz Valipour, Sahar Davari, Raheleh Farahzadi, Shahram Pourrasol, Niloofar Mehran, Khadijeh Dizaji Asl, Seyed Mansour Altaha, Zahra Hojjati, Hojjatollah Nozad Charoudeh.

Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34+ and CD38- phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34+ and CD34- cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34+ , CD34- and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34+ AML cells compared to CD34- AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.

Keywords: acute myeloid leukemia; apoptosis; leukemia stem cells; mitochondria; tigecycline

DOI: https://doi.org/10.1002/cbf.3888