Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria

EMBO J. 2011 May 24;30(13):2545-56. doi: 10.1038/emboj.2011.169.


m-AAA proteases exert dual functions in the mitochondrial inner membrane: they mediate the processing of specific regulatory proteins and ensure protein quality control degrading misfolded polypeptides to peptides. Loss of these activities leads to neuronal cell death in several neurodegenerative disorders. However, it is unclear how the m-AAA protease chooses between specific processing and complete degradation. A central and conserved function of the m-AAA protease is the processing of the ribosomal subunit MrpL32, which regulates ribosome biogenesis and the formation of respiratory complexes. Here, we demonstrate that the formation of a tightly folded domain harbouring a conserved CxxC-X(9)-CxxC sequence motif halts degradation initiated from the N-terminus and triggers the release of mature MrpL32. Oxidative stress impairs folding of MrpL32, resulting in its degradation by the m-AAA protease and decreased mitochondrial translation. Surprisingly, MrpL32 folding depends on its mitochondrial targeting sequence. Presequence-assisted folding of MrpL32 requires the complete import of the MrpL32 precursor before maturation occurs and therefore explains the need for post-translocational processing by the m-AAA protease rather than co-translocational cleavage by the general mitochondrial processing peptidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / physiology*
  • Catalytic Domain / genetics
  • Deinococcus / enzymology
  • Deinococcus / metabolism
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Metalloendopeptidases / physiology
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Organisms, Genetically Modified
  • Protein Binding / physiology
  • Protein Folding*
  • Protein Processing, Post-Translational
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Ribosomal Proteins / chemistry
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Analysis, Protein
  • Sequence Homology, Amino Acid


  • MrpL32 protein, S cerevisiae
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Metalloendopeptidases
  • m-AAA proteases