Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations.
About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvi...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-04-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3080857?pdf=render |
| _version_ | 1818609570166079488 |
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| author | Raquel Moreno-Loshuertos Gustavo Ferrín Rebeca Acín-Pérez M Esther Gallardo Carlo Viscomi Acisclo Pérez-Martos Massimo Zeviani Patricio Fernández-Silva José Antonio Enríquez |
| author_facet | Raquel Moreno-Loshuertos Gustavo Ferrín Rebeca Acín-Pérez M Esther Gallardo Carlo Viscomi Acisclo Pérez-Martos Massimo Zeviani Patricio Fernández-Silva José Antonio Enríquez |
| author_sort | Raquel Moreno-Loshuertos |
| collection | DOAJ |
| description | About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNA(Ile) that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both. |
| first_indexed | 2024-12-16T15:00:38Z |
| format | Article |
| id | doaj.art-edf364bf23964d438441d5fb78b7a745 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-16T15:00:38Z |
| publishDate | 2011-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-edf364bf23964d438441d5fb78b7a7452022-12-21T22:27:18ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-04-0174e100137910.1371/journal.pgen.1001379Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations.Raquel Moreno-LoshuertosGustavo FerrínRebeca Acín-PérezM Esther GallardoCarlo ViscomiAcisclo Pérez-MartosMassimo ZevianiPatricio Fernández-SilvaJosé Antonio EnríquezAbout half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNA(Ile) that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both.http://europepmc.org/articles/PMC3080857?pdf=render |
| spellingShingle | Raquel Moreno-Loshuertos Gustavo Ferrín Rebeca Acín-Pérez M Esther Gallardo Carlo Viscomi Acisclo Pérez-Martos Massimo Zeviani Patricio Fernández-Silva José Antonio Enríquez Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. PLoS Genetics |
| title | Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. |
| title_full | Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. |
| title_fullStr | Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. |
| title_full_unstemmed | Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. |
| title_short | Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. |
| title_sort | evolution meets disease penetrance and functional epistasis of mitochondrial trna mutations |
| url | http://europepmc.org/articles/PMC3080857?pdf=render |
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