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LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation

Rubalcava-Gracia, Diana ; Bubb, Kristina ; Levander, Fredrik LU orcid ; Burr, Stephen P ; August, Amelie V ; Chinnery, Patrick F ; Koolmeister, Camilla and Larsson, Nils-Göran (2024) In Nucleic Acids Research
Abstract

In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation... (More)

In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.

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author
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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Nucleic Acids Research
publisher
Oxford University Press
external identifiers
  • pmid:39087558
ISSN
1362-4962
DOI
10.1093/nar/gkae662
language
English
LU publication?
yes
id
5db83802-b53c-48c9-afc7-5cccd8b5dfb5
date added to LUP
2024-08-27 08:57:18
date last changed
2024-09-12 11:05:48
@article{5db83802-b53c-48c9-afc7-5cccd8b5dfb5,
  abstract     = {{<p>In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.</p>}},
  author       = {{Rubalcava-Gracia, Diana and Bubb, Kristina and Levander, Fredrik and Burr, Stephen P and August, Amelie V and Chinnery, Patrick F and Koolmeister, Camilla and Larsson, Nils-Göran}},
  issn         = {{1362-4962}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation}},
  url          = {{http://dx.doi.org/10.1093/nar/gkae662}},
  doi          = {{10.1093/nar/gkae662}},
  year         = {{2024}},
}