DELE1, also known as DAP3 Binding Cell Death Enhancer 1, is a mitochondrial protein. It plays a crucial role in relaying mitochondrial stress to the cytosol, activating the integrated stress response (ISR) via the OMA1-DELE1-HRI pathway [1,2]. This pathway leads to the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), induction of the transcription factor ATF4, and is essential for maintaining cellular homeostasis in response to mitochondrial dysfunction [1].

In mouse models, Dele1 knockout in the heart shows that it is dispensable for cardiac development and function under normal conditions. However, it is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy [3].

In mitochondrial myopathy mouse models, the absence of Dele1 leads to dysregulated protein synthesis, protein misfolding, and failure to grow and survive, highlighting its role in maintaining muscle proteostasis and promoting growth and survival [4,5].

In monosomy 5/del(5q) AML, the partial loss of DELE1 expression reduces the sensitivity to mitochondrial stress in AML cells, suggesting it could be a new driver mechanism in this disease [6].

In conclusion, DELE1 is crucial for maintaining cellular homeostasis in response to mitochondrial stress. Studies using Dele1 knockout or conditional knockout mouse models have revealed its protective role in mitochondrial cardiomyopathy and mitochondrial myopathy, and its potential role in monosomy 5/del(5q) AML. These findings enhance our understanding of the biological functions of DELE1 and its implications in diseases related to mitochondrial dysfunction.