Integrated analysis of transcriptional and metabolic responses to mitochondrial stress

Mitochondrial stress arises from a variety of sources, including accumulation of mutations in mitochondrial DNA, generation of reactive oxygen species, and insufficient supplies of oxygen or fuel. Cells utilize multiple pathways to respond to mitochondrial injury, including mitophagy, mitochondrial fusion, and the integrated stress response / mitochondrial unfolded protein response. However, the integration of transcriptional and metabolic signatures of distinct types of mitochondrial stress are still not well defined. We defined how primary human fibroblasts respond to a panel of well-characterized inhibitors that target key pathways in the mitochondria, using sub-lethal doses to trigger adaptive stress responses. By combining metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, SQUID, to infer molecular triggers of mitochondrial dysfunction in other datasets. Using SQUID, we globally investigated mitochondrial stress in the TCGA PanCancer Atlas and identified defects in pyruvate import in IDH1 mutant glioma. Altogether, these studies provide a comprehensive resource detailing cellular stress responses that safeguard mitochondrial health.