Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we showed that the ISR has multiple arms and developed an ISR ^GDF15 index quantifying the GDF15 arm of ISR activation in human cells. The ISR ^GDF15 index was validated using optogenetic activation of the ISR protein kinase R (PKR) in a stable cell line, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deployed the ISR ^GDF15 index across 44 postmortem human tissues, reporting that the ISR ^GDF15 was upregulated in the heart of individuals who died of an acute cause in the emergency room, whereas it was preferentially upregulated in the brain of individuals who died as inpatients after protracted hospital stays. ISR ^GDF15 was also moderately, positively correlated with age across all tissues. These data highlight multiple distinct ISR pathways and clarify which genes are related to the GDF15 arm of the ISR, yielding an ISR ^GDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues. Ultimately, we expand our knowledge of the GDF15 arm of the ISR in humans, show its inducibility by the ISR kinase PKR, and demonstrate its applicability to detect ISR activation in specific human tissues.