The role of the nucleus in the control of mitochondrial precursor proteins in yeast

Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.