Deeper Dive
My project defined the stress-responsive signaling pathways activated in response to mitochondrial proteostasis disruption induced by chronic genetic perturbation. To achieve this, I developed a novel gene set profiling approach that monitors the expression of gene sets comprising transcriptional targets regulated downstream of stress-responsive signaling pathways in CRISPRi Perturb-seq datasets from K562 cells. This analysis remarkably identified the integrated stress response (ISR) as the only stress-responsive signaling pathway activated by this type of genetic mitochondrial proteostasis disruption. This selectivity was confirmed transcriptome-wide, indicating that mitochondrial proteostasis disruptions preferentially activate ISR signaling. I then expanded the study to show that CRISPRi depletion of all mitochondrial proteins similarly demonstrated preferential activation of the ISR over other stress-responsive signaling pathways. Collectively, these results identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronic mitochondrial proteostasis stress, underscoring the need to better understand its critical role in adapting mitochondrial proteostasis and function in both health and disease. What began as an interest in learning about metabolic diseases, sparked by my aunt’s experience with type 1 diabetes, has grown into a mission to help scientists develop therapeutics to treat her and millions of other patients worldwide.