Gene Expression and Drug Sensitivity Analysis of Mitochondrial Chaperones Reveals That HSPD1 and TRAP1 Expression Correlates with Sensitivity to Inhibitors of DNA Replication and Mitosis

Simple Summary Mitochondria-the energy-producing organelles of a cell-contain numerous enzymes essential for many cellular processes. Enzymes, which are imported into the mitochondria in linear form, must be properly folded to become functional. It is known that the folding is facilitated by molecules known as chaperones. However, it is not known whether the folding of specific mitochondrial proteins (enzymes) is dependent on particular mitochondrial chaperones or whether specific chaperones are linked to drug sensitivity in tumor cells. Here, we analyzed drug sensitivity and gene expression data for cancer cells treated with various drugs and found that levels of certain chaperones correlated with the cells' response to different drug classes. Additionally, we experimentally confirmed our findings by showing that a certain mitochondrial chaperone could protect tumor cells from one type of drug while making them more sensitive to another. These findings lay down the groundwork for understanding the roles of mitochondrial chaperones in cancer therapeutics, with implications for personalized medicine. Mitochondria-critical metabolic hubs in eukaryotic cells-are involved in a wide range of cellular functions, including differentiation, proliferation, and death. Mitochondria import most of their proteins from the cytosol in a linear form, after which they are folded by mitochondrial chaperones. However, despite extensive research, the extent to which the function of particular chaperones is essential for maintaining specific mitochondrial and cellular functions remains unknown. In particular, it is not known whether mitochondrial chaperones influence the sensitivity to drugs used in the treatment of cancers. By mining gene expression and drug sensitivity data for cancer cell lines from publicly available databases, we identified mitochondrial chaperones whose expression is associated with sensitivity to oncology drugs targeting particular cellular pathways in a cancer-type-dependent manner. Importantly, we found the expression of TRAP1 and HSPD1 to be associated with sensitivity to inhibitors of DNA replication and mitosis. We confirmed experimentally that the expression of HSPD1 is associated with an increased sensitivity of ovarian cancer cells to drugs targeting mitosis and a reduced sensitivity to drugs promoting apoptosis. Taken together, our results support a model in which particular mitochondrial pathways hinge upon specific mitochondrial chaperones and provide the basis for understanding selectivity in mitochondrial chaperone-substrate specificity.