Abstract 1916 Eukaryotic cell death is mediated by arginyltransferase 1 in a mitochondrial-dependent pathway

The regulation of cell death in eukaryotic cells plays a crucial role in regulating the stress response, and response to signals. Recent studies highlight the dependence of stress-induced cell death events on the activity of arginyltransferase1 (ATE1), an evolutionarily conserved enzyme that initiates protein degradation through a posttranslational modification known as arginylation. Despite the significance of ATE1 in this process, the precise mechanisms through which it fulfills this role remain largely elusive. In our investigation using budding yeast as a test model, we uncovered a noteworthy phenomenon: under oxidative stress, cytosolic ATE1 increases its localization into mitochondria and that preventing its mitochondrial localization prevents its associated cell death. Intriguingly, our study has also revealed that ATE1-mediated cell death operates independently of mitochondrial Electron Transport Chain (ETC) activity and the traditional caspase pathway. Instead, we have found that ATE1-mediated cell death is reliant on certain mitochondrial permeability pore components and the subsequent release of apoptosis-inducing factor. From these findings, we assert that ATE1 emerges as a novel apoptosis regulator, uniquely utilizing a specific mitochondrial pathway. This discovery opens new avenues for understanding and potentially manipulating apoptosis regulation for therapeutic purposes. This study is supported in part by NIGMS/NIH R01GM138557 and a University of Miami startup funding awarded to FZ.