Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster

I. Pimenta De Castro, A. C. Costa, D. Lam, R. Tufi, V. Fedele, N. Moisoi, D. Dinsdale, E. Deas, S. H Y Loh, L. M. Martins

Research output: Contribution to journalArticlepeer-review


Protein misfolding has a key role in several neurological disorders including Parkinson's disease. Although a clear mechanism for such proteinopathic diseases is well established when aggregated proteins accumulate in the cytosol, cell nucleus, endoplasmic reticulum and extracellular space, little is known about the role of protein aggregation in the mitochondria. Here we show that mutations in both human and fly PINK1 result in higher levels of misfolded components of respiratory complexes and increase in markers of the mitochondrial unfolded protein response. Through the development of a genetic model of mitochondrial protein misfolding employing Drosophila melanogaster, we show that the in vivo accumulation of an unfolded protein in mitochondria results in the activation of AMP-activated protein kinase-dependent autophagy and phenocopies of pink1 and parkin mutants. Parkin expression acts to clear mitochondria with enhanced levels of misfolded proteins by promoting their autophagic degradation in vivo, and refractory to Sigma P (ref(2)P), the Drosophila orthologue of mammalian p62, is a critical downstream effector of this quality control pathway. We show that in flies, a pathway involving pink1, parkin and ref(2)P has a role in the maintenance of a viable pool of cellular mitochondria by promoting organellar quality control.

Original languageEnglish
Pages (from-to)1308-1316
Number of pages9
JournalCell Death and Differentiation
Issue number8
Publication statusPublished - Aug 2012


  • autophagy
  • Drosophila
  • mitochondria
  • unfolded proteins

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology


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