Selective degradation of an immature mitochondrial matrix protein occurs via a non-canonical N-end rule pathway — ASN Events
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  2. Session 5: Poster Session A
  3. Selective degradation of an immature mitochondrial matrix protein occurs via a non-canonical N-end rule pathway

Selective degradation of an immature mitochondrial matrix protein occurs via a non-canonical N-end rule pathway (#188)

Tamanna Saiyed 1 2 , David D Dougan 1 , Kaye N Truscott 1
  1. La Trobe University, Melbourne, VIC, Australia
  2. Cooperative Research Centre for Biomarker Translation, Melbourne, Victoria, Australia

The vast majority of mitochondrial proteins are nuclear-encoded, synthesised in the cytosol and directed to the organelle via their N-terminal targeting signals. Within the mitochondrial matrix, the processing of the N-terminal presequence occurs, in most cases, in a single step mediated by matrix processing peptidase (MPP). However, some preproteins require an additional processing step to generate the mature protein catalysed by a conserved eukaryotic metalloendopeptidase, mitochondrial intermediate peptidase (MIP/Oct1)1. Recently a novel processing exopeptidase, intermediate cleaving peptidase (Icp55) was identified in yeast2. Icp55 is responsible for the removal of a single amino acid residue from intermediates generated by MPP with 52 substrates being identified to date2,3. Loss of Icp55 function generates a subset of immature matrix proteins that expose an N-terminal residue resembling an N-terminal degradation signal (or N-degron) found in prokaryotes4. Importantly, these immature matrix proteins are unstable in yeast mitochondria suggesting the existence of an N-end rule pathway of protein degradation in mitochondria2,4. Mutations in the human mitochondrial homolog of Icp55, known as aminopeptidase3 (APP3m) are associated with disease including nephrophthisis and complex I deficiencies. However, its role in presequence processing including its substrate repertoire and specificity currently remains unknown. We have investigated the processing and turnover of a candidate APP3m substrate. Our data suggests that the processing intermediate is degraded by a non-canonical N-end rule pathway, mediated by a matrix AAA+ protease. We speculate that loss of APP3m function results in the selective and premature degradation of one or more key matrix proteins resulting in mitochondrial dysfunction.

  1. Vögtle, F-N., Prinz, C., Kellermann, J., Lottspeich, F., Pfanner, N., and Meisinger, C. (2011) Mitochondrial protein turnover: role of the precursor intermediate peptidase Oct1 in protein stabilization. Molecular Biology of Cell 12: 2135-2143

  2. Vögtle, F-N., Wortelkamp, S., Zahedi, R.P., Becker, D., Leidhold, C., Gevaert, K., Kellermann, J., Voos, W., Sickmann, A., Pfanner, N., and Meisinger, C. (2009) Global Analysis of the Mitochondrial N-Proteome Identifies a Processing Peptidase Critical for Protein Stability. Cell 139: 428-439

  3. Venne, A.S., Vogtle, F.N., Meisinger, C., Sickmann, A., and Zahedi, R.P. (2013) Novel highly sensitive, specific, and straightforward strategy for comprehensive N-terminal proteomics reveals unknown substrates of the mitochondrial peptidase Icp55 Journal of Proteome Research 12: 3823-3830

  4. Dougan, D.A., Truscott, K.N., and Zeth, K. (2010) The bacterial N-end rule pathway: expect the unexpected. Molecular Microbiology 76: 545-558