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

Author:

Rubalcava-Gracia Diana1ORCID,Bubb Kristina1,Levander Fredrik2ORCID,Burr Stephen P3,August Amelie V1,Chinnery Patrick F3,Koolmeister Camilla1,Larsson Nils-Göran1ORCID

Affiliation:

1. Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm , Sweden

2. Department en Immunotechnology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University , Lund , Sweden

3. Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus , Cambridge, UK; Medical Research Council Mitochondrial Biology Unit,University of Cambridge, Cambridge Biomedical Campus, Cambridge , UK

Abstract

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 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.

Funder

Swedish Research Council

Swedish Cancer Foundation

Knut and Alice Wallenberg

Swedish Brain Foundation

European Research Council

Swedish Diabetes Foundation

Novo Nordisk Foundation

Swedish government

Max Planck Society

Publisher

Oxford University Press (OUP)

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