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, mainly through the OMA1-DELE1-HRI pathway. This pathway activates the integrated stress response (ISR) by phosphorylating eukaryotic translation initiation factor 2α (eIF2α), leading to the induction of the transcription factor ATF4 [1,3]. It is also involved in a mitochondrial iron-responsive pathway [2].

In mitochondrial myopathy mouse models, disruption of Dele1 leads to failure in growth and survival, as it is essential for maintaining muscle proteostasis and translation-associated homeostasis in response to mitochondrial stress [5,6]. In mitochondrial cardiomyopathy mouse models, Dele1 is dispensable under baseline conditions but is crucial for mediating an adaptive response to mitochondrial dysfunction-triggered stress, playing a protective role [4]. In monosomy 5/del(5q) AML, partial loss of DELE1 expression reduces the sensitivity of AML cells to mitochondrial stress, suggesting DELE1 haploinsufficiency as a new driver mechanism [7].

In conclusion, DELE1 is vital for maintaining cellular homeostasis in response to mitochondrial stress. Its study using gene knockout or conditional knockout mouse models has revealed its protective role in mitochondrial myopathy and cardiomyopathy, and its potential role in monosomy 5/del(5q) AML. Understanding DELE1's function provides insights into the mechanisms of diseases related to mitochondrial dysfunction.

References:

1. Guo, Xiaoyan, Aviles, Giovanni, Liu, Yi, Correia, M Almira, Kampmann, Martin. 2020. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. In Nature, 579, 427-432. doi:10.1038/s41586-020-2078-2. https://pubmed.ncbi.nlm.nih.gov/32132707/

2. Sekine, Yusuke, Houston, Ryan, Eckl, Eva-Maria, Jae, Lucas T, Sekine, Shiori. . A mitochondrial iron-responsive pathway regulated by DELE1. In Molecular cell, 83, 2059-2076.e6. doi:10.1016/j.molcel.2023.05.031. https://pubmed.ncbi.nlm.nih.gov/37327776/

3. Fessler, Evelyn, Eckl, Eva-Maria, Schmitt, Sabine, Zischka, Hans, Jae, Lucas T. 2020. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. In Nature, 579, 433-437. doi:10.1038/s41586-020-2076-4. https://pubmed.ncbi.nlm.nih.gov/32132706/

4. Huynh, Helen, Zhu, Siting, Lee, Sharon, Evans, Sylvia M, Fang, Xi. 2022. DELE1 is protective for mitochondrial cardiomyopathy. In Journal of molecular and cellular cardiology, 175, 44-48. doi:10.1016/j.yjmcc.2022.12.003. https://pubmed.ncbi.nlm.nih.gov/36539111/

5. Lin, Hsin-Pin, Petersen, Jennifer D, Gilsrud, Alexandra J, Pacold, Michael E, Narendra, Derek P. 2024. DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy. In The EMBO journal, 43, 5548-5585. doi:10.1038/s44318-024-00242-x. https://pubmed.ncbi.nlm.nih.gov/39379554/

6. Lin, Hsin-Pin, Petersen, Jennifer D, Gilsrud, Alexandra J, Pacold, Michael E, Narendra, Derek P. 2024. DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.02.29.582673. https://pubmed.ncbi.nlm.nih.gov/38529505/

7. Spinella, Jean-François, Chagraoui, Jalila, Moison, Céline, Hébert, Josée, Sauvageau, Guy. 2023. DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML. In Leukemia, 38, 530-537. doi:10.1038/s41375-023-02107-4. https://pubmed.ncbi.nlm.nih.gov/38102204/