Mol. Cell https://doi.org/10.1016/j.molcel.2019.09.026 (2019)
Nuclear-encoded mitochondrial proteins are directed to their destination by N-terminal leader peptides, which are removed by the presequence protease MPP, localized in the mitochondrial matrix. Improper processing of precursor proteins through loss of MPP function is thought to impair protein stability. Using a yeast strain containing a temperature-sensitive MPP, Poveda-Huertes et al. revealed that deactivation of MPP at higher temperatures induced abnormal accumulation of unprocessed precursor proteins that formed insoluble aggregates inside mitochondria but did not alter mitochondrial function or cell survival. RNA-seq analysis revealed that genes associated with protein folding and refolding were upregulated. The authors used a synthetic lethality assay to identify nuclear protein Rox1 as a critical mediator of survival upon loss of MPP activity. Loss of MPP function resulted in the translocation of Rox1 into the mitochondria, where it binds mitochondrial DNA, thereby stabilizing de novo synthesized DNA and enhancing transcription and translation. This study reveals a new early mitochondrial unfolding response and stresses the role of intracellular communication in regulating proteostasis.