Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.

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