The overarching goal of our research program is to understand the molecular and cellular mechanisms of the mitochondrial stress response in mammalian cells and its relevance to disease pathogenesis. Studies in patients, animals, and cultured cells have consistently indicated an activation of the integrated stress response (ISR) as a signature of mitochondrial dysfunction. The ISR converges on the phosphorylation of eIF2α. The outcomes of the ISR include reducing global protein translation but paradoxically increasing the translation of a subset of genes containing upstream open reading frames (uORFs), such as activating transcriptional factor 4 (ATF4). How mitochondrial dysfunction triggers the ISR has been a major open question for the past two decades. It is also not clear whether the ISR triggered by mitochondrial dysfunction is protective or whether it contributes to the pathogenesis of the disease.

An unbiased CRISPRi-based genetic screen using an ATF4 translational reporter cell line allowed us to identify a novel signaling pathway that triggers the ISR in response to mitochondrial stress. Using biochemistry and cell biology approaches, we have demonstrated that DELE1, a little-characterized mitochondrially localized protein is cleaved in an OMA-1-dependent manner upon mitochondrial stress. Cleaved DELE1 exits mitochondria and accumulates in the cytosol, where it interacts with and stimulates one of the four eIF2α kinases, HRI. Interestingly, the OMA-DELE1-HRI pathway is adaptive under some mitochondrial stress conditions but maladaptive under others.

Applying CRISPR-based functional genomics, biochemistry, and molecular and cellular approaches, we are investigating how OMA1-DELE1-HRI is regulated.