Mechanistic Elucidation of Mitochondrial Stress Response in Human Cells

PROJECT SUMMARY/ABSTRACT Mitochondria play essential roles in eukaryotic cells. However, they are often subject to stress originated from various sources, both intrinsic and extrinsic. In response to such stress, cells activate a diverse array of stress response mechanisms collectively known as the mitochondrial stress response, aimed at restoring mitochondrial homeostasis and preserving overall cellular fitness. Our recent work has uncovered a key mitochondrial stress response pathway involving the integrated stress response (ISR), a cellular strategy for coping with diverse stress conditions. Despite distinct triggering mechanisms, all the ISR pathways converge on the phosphorylation of eIF2a by four stress-specific kinases (PKR, GCN2, HRI and PERK). This phosphorylation event leads to an attenuation of global protein synthesis while upregulating the expression of stress response transcription factor like ATF4. Our research has revealed an OMA1-DELE1-HRI signaling cascade as a distinct link between mitochondrial stress and the ISR, offering a unique therapeutic target for manipulating the ISR in disorders associated with mitochondrial dysfunction. However, we currently lack a comprehensive understanding of how cells integrate mitochondrial stress programs to maintain a homeostatic mitochondrial network. The long-term goal of our lab is to comprehensively elucidate molecular and cellular mechanisms of the mitochondrial stress response spanning from the molecular mechanisms of stress sensing and transmitting to the ultimate outcomes. Recent findings by us and others highlighted critical roles of protein trafficking in sensing and relaying mitochondrial stress. By leveraging reporter-based assays, CRISPR screens, reconstituted cell-free assays and proteomics approaches, a primary objective of our lab is to elucidate the molecular mechanisms governing protein dynamics during mitochondrial stress. While emerging as a primary mitochondrial stress response under various stress conditions in a wide range of cell types, there remains a significant gap in understanding how the OMA1-DELE1-HRI-mediated ISR integrates with other mitochondrial stress response programs to maintain mitochondrial homeostasis. Another key objective of our lab is to systematically elucidate the intricate mechanisms involved in maintaining a homeostatic mitochondrial network. Considering that mitochondrial dysfunction is a major hallmark of numerous diseases such as primary mitochondrial diseases and neurodegenerative diseases, our mechanistic investigations into the mitochondrial stress response are anticipated to significantly advance our understanding of these pathological conditions and will potentially identify novel therapeutic targets to mitigate their impacts.