Evolution meets disease: Penetrance and functional epistasis of mitochondrial tRNA mutations

Raquel Moreno-Loshuertos, Gustavo Ferrín, Rebeca Acín-Pérez, M. Esther Gallardo, Carlo Viscomi, Acisclo Pérez-Martos, Massimo Zeviani, Patricio Fernández-Silva, José Antonio Enríquez

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 tRNAIle 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.

Original languageEnglish
Article numbere1001379
JournalPLoS Genetics
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

epistasis
penetrance
Penetrance
Transfer RNA
mutation
Mutation
fixation
gene
mice
RNA, Transfer, Ile
Genes
genes
Isoleucine
Organelle Biogenesis
isoleucine
Mitochondrial DNA
human diseases
mitochondrial DNA
folding
allele

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Moreno-Loshuertos, R., Ferrín, G., Acín-Pérez, R., Gallardo, M. E., Viscomi, C., Pérez-Martos, A., ... Enríquez, J. A. (2011). Evolution meets disease: Penetrance and functional epistasis of mitochondrial tRNA mutations. PLoS Genetics, 7(4), [e1001379]. https://doi.org/10.1371/journal.pgen.1001379

Evolution meets disease : Penetrance and functional epistasis of mitochondrial tRNA mutations. / Moreno-Loshuertos, Raquel; Ferrín, Gustavo; Acín-Pérez, Rebeca; Gallardo, M. Esther; Viscomi, Carlo; Pérez-Martos, Acisclo; Zeviani, Massimo; Fernández-Silva, Patricio; Enríquez, José Antonio.

In: PLoS Genetics, Vol. 7, No. 4, e1001379, 04.2011.

Research output: Contribution to journalArticle

Moreno-Loshuertos, R, Ferrín, G, Acín-Pérez, R, Gallardo, ME, Viscomi, C, Pérez-Martos, A, Zeviani, M, Fernández-Silva, P & Enríquez, JA 2011, 'Evolution meets disease: Penetrance and functional epistasis of mitochondrial tRNA mutations', PLoS Genetics, vol. 7, no. 4, e1001379. https://doi.org/10.1371/journal.pgen.1001379
Moreno-Loshuertos R, Ferrín G, Acín-Pérez R, Gallardo ME, Viscomi C, Pérez-Martos A et al. Evolution meets disease: Penetrance and functional epistasis of mitochondrial tRNA mutations. PLoS Genetics. 2011 Apr;7(4). e1001379. https://doi.org/10.1371/journal.pgen.1001379
Moreno-Loshuertos, Raquel ; Ferrín, Gustavo ; Acín-Pérez, Rebeca ; Gallardo, M. Esther ; Viscomi, Carlo ; Pérez-Martos, Acisclo ; Zeviani, Massimo ; Fernández-Silva, Patricio ; Enríquez, José Antonio. / Evolution meets disease : Penetrance and functional epistasis of mitochondrial tRNA mutations. In: PLoS Genetics. 2011 ; Vol. 7, No. 4.
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