TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins
Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucle...
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MDPI AG
2023-05-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/5/1043 |
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| author | Thet Fatica Turaya Naas Urszula Liwak Hannah Slaa Maryam Souaid Brianna Frangione Ribal Kattini Antoine Gaudreau-Lapierre Laura Trinkle-Mulcahy Pranesh Chakraborty Martin Holcik |
| author_facet | Thet Fatica Turaya Naas Urszula Liwak Hannah Slaa Maryam Souaid Brianna Frangione Ribal Kattini Antoine Gaudreau-Lapierre Laura Trinkle-Mulcahy Pranesh Chakraborty Martin Holcik |
| author_sort | Thet Fatica |
| collection | DOAJ |
| description | Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (<i>TRNT1</i>), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that <i>TRNT1</i> deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins. |
| first_indexed | 2024-03-11T03:43:14Z |
| format | Article |
| id | doaj.art-fab283e1c6674bfcb1cabe2d023cea3a |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T03:43:14Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-fab283e1c6674bfcb1cabe2d023cea3a2023-11-18T01:29:41ZengMDPI AGGenes2073-44252023-05-01145104310.3390/genes14051043TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct ProteinsThet Fatica0Turaya Naas1Urszula Liwak2Hannah Slaa3Maryam Souaid4Brianna Frangione5Ribal Kattini6Antoine Gaudreau-Lapierre7Laura Trinkle-Mulcahy8Pranesh Chakraborty9Martin Holcik10Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, CanadaChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, CanadaChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, CanadaChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, CanadaDepartment of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, CanadaDepartment of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, CanadaDepartment of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, CanadaDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, CanadaDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, CanadaChildren’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, CanadaDepartment of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, CanadaMitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (<i>TRNT1</i>), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that <i>TRNT1</i> deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins.https://www.mdpi.com/2073-4425/14/5/1043SIFDTRNT1tiRNACCA addingoxidative stressSILAC |
| spellingShingle | Thet Fatica Turaya Naas Urszula Liwak Hannah Slaa Maryam Souaid Brianna Frangione Ribal Kattini Antoine Gaudreau-Lapierre Laura Trinkle-Mulcahy Pranesh Chakraborty Martin Holcik TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins Genes SIFD TRNT1 tiRNA CCA adding oxidative stress SILAC |
| title | TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins |
| title_full | TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins |
| title_fullStr | TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins |
| title_full_unstemmed | TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins |
| title_short | TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins |
| title_sort | trnt 1 deficiency is associated with loss of trna integrity and imbalance of distinct proteins |
| topic | SIFD TRNT1 tiRNA CCA adding oxidative stress SILAC |
| url | https://www.mdpi.com/2073-4425/14/5/1043 |
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