ArticleHuman molecular genetics2014
A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 74 citations in OpenAlex.
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- Transcription, Maturation and Degradation of Mitochondrial RNA: Implications for Innate Immune Response.Biomolecules · 2025Review
- The human mitochondrial mRNA structurome reveals mechanisms of gene expression.Science (New York, N.Y.) · 2024Article
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- Mitochondrial RNA maturation.RNA biology · 2024Review
- TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.Acta pharmacologica Sinica · 2023Article
- Translation in Mitochondrial Ribosomes.Methods in molecular biology (Clifton, N.J.) · 2023Article
- RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.Nucleic acids research · 2022Article
- Organization and expression of the mammalian mitochondrial genome.Nature reviews. Genetics · 2022Review
- ANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing.Nature communications · 2022Article
- Review
- The Bidirectional Link Between RNA Cleavage and Polyadenylation and Genome Stability: Recent Insights From a Systematic Screen.Frontiers in genetics · 2022Review
- Article
- Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers.International journal of molecular sciences · 2021Article
- RNA Granules in the Mitochondria and Their Organization under Mitochondrial Stresses.International journal of molecular sciences · 2021Review
- Human Mitochondrial RNA Processing and Modifications: Overview.International journal of molecular sciences · 2021Review
- Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency.Nucleic acids research · 2021Article
- Mechanisms and regulation of protein synthesis in mitochondria.Nature reviews. Molecular cell biology · 2021Review
- Functions and mechanisms of RNA tailing by metazoan terminal nucleotidyltransferases.Wiley interdisciplinary reviews. RNA · 2021Review
- Identification of Parkinson's Disease-Causing Genes via Omics Data.Frontiers in genetics · 2021Article
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
The p.N478D missense mutation in human mitochondrial poly(A) polymerase (mtPAP) has previously been implicated in a form of spastic ataxia with optic atrophy. In this study, we have investigated fibroblast cell lines established from family members. The homozygous mutation resulted in the loss of polyadenylation of all mitochondrial transcripts assessed; however, oligoadenylation was retained. Interestingly, this had differential effects on transcript stability that were dependent on the particular species of transcript. These changes were accompanied by a severe loss of oxidative phosphorylation complexes I and IV, and perturbation of de novo mitochondrial protein synthesis. Decreases in transcript polyadenylation and in respiratory chain complexes were effectively rescued by overexpression of wild-type mtPAP. Both mutated and wild-type mtPAP localized to the mitochondrial RNA-processing granules thereby eliminating mislocalization as a cause of defective polyadenylation. In vitro polyadenylation assays revealed severely compromised activity by the mutated protein, which generated only short oligo(A) extensions on RNA substrates, irrespective of RNA secondary structure. The addition of LRPPRC/SLIRP, a mitochondrial RNA-binding complex, enhanced activity of the wild-type mtPAP resulting in increased overall tail length. The LRPPRC/SLIRP effect although present was less marked with mutated mtPAP, independent of RNA secondary structure. We conclude that (i) the polymerase activity of mtPAP can be modulated by the presence of LRPPRC/SLIRP, (ii) N478D mtPAP mutation decreases polymerase activity and (iii) the alteration in poly(A) length is sufficient to cause dysregulation of post-transcriptional expression and the pathogenic lack of respiratory chain complexes.
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