The mitochondrial oxidoreductase Mia40 modulates the toxicity of cytosolic protein aggregates Anna Schlagowski1, Ralf Braun2, Johannes M. Herrmann1 1, Cell Biology, University of Kaiserslautern, Germany; 2, Cell Biology, University of Bayreuth, Germany Mitochondrial biogenesis depends on the translation of hundreds of precursor proteins in the cytosol which have to be targeted and transported to mitochondria. In my work I investigate mitochondrial precursor proteins in the cytosol of yeast under proteotoxic stress conditions caused by the accumulation of aggregation-prone poly-Q proteins. The poly-Q stretch used is derived from a Q97-variant of huntingtin that causes Huntington's disease in humans. This neurodegenerative disease is characterized by the death of neurons in specific parts in the brain. The cellular events which lead to cell death remain largely elusive. First, I tested whether the accumulation of Q97 interferes with mitochondrial protein import. To this end, I applied an in vivo reporter assay which monitors the accumulation of mitochondrial precursor proteins in the cytosol by a growth test. Interestingly, I observed that mitochondrial precursor proteins accumulate in the cytosol upon Q97 expression. The accumulation of these proteins coincided with the toxic effects of the proteins. Shorter, non-toxic huntingtin versions (Q25) did not lead to precursor accumulation in the cytosol. It was recently reported that a reduced activity of the MIA pathway, which imports proteins in the mitochondrial intermembrane space (IMS), leads to the induction of cytosolic chaperones and proteasome subunits (Wrobel et al. 2015. Nature 524, 485f). Interestingly, we observed that mia40 mutants which further increase the levels of mitochondrial precursors in the cytosol, strongly increase the toxicity of Q97. Even more surprising was our observation that the overexpression of Mia40 largely suppresses Q97-mediated toxicity. This is confirmed by a previous genome-wide study for Q97 suppressors which identified a large number of IMS proteins (Mason et al. 2013. Nature Genetics 45, 1249f). This suggests that Mia40 can modulate the effects of cytosolic protein aggregates via a so far unknown mechanism. I am currently exploring how IMS proteins can increase the tolerance against aggregation-prone proteins in the cytosol. My first results suggest that overexpression of Mia40 strongly increases the levels of polyQ proteins that can accumulate in soluble form in the cytosol.
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