MORN4, a protein-encoding gene, contains MORN (membrane occupation and recognition nexus) repeats. It is involved in multiple biological functions. It has been associated with mitochondrial dynamics, mitophagy, protein-protein interactions, and axonal degeneration [1,2,3,4]. In terms of associated pathways, it is linked to the Rho-associated protein kinase 2 (ROCK2)-mediated phosphorylation of MFN2 in the context of mitochondrial-related processes [1]. MORN4 is important as it contributes to maintaining cellular homeostasis, especially in cardiomyocytes and neurons [1,4]. Genetic models, such as gene-knockout models, have been crucial for studying its functions.

In a mouse model of myocardial infarction (MI), knockdown of MORN4 accelerated cardiac injury, fibrosis, and deteriorated cardiac function, indicating its protective role in cardiomyocytes against ischemic injury [1]. Mechanistically, MORN4 directly binds to MFN2 and promotes its phosphorylation at S442 through ROCK2, mediating beneficial mitophagy induced by mitochondrial dynamics [1]. In Drosophila, knockdown of retinophilin (rtp, the ortholog of MORN4 in Drosophila) protected axons from taxol-induced degeneration, and loss-of-function mutants of rtp replicated this protection. Similarly, knockdown of MORN4 in mouse sensory axons following axotomy delayed axonal degeneration, demonstrating its conserved function in promoting axonal degeneration [4].

In conclusion, MORN4 plays essential roles in protecting cardiomyocytes from ischemic injury through regulating mitochondrial dynamics and mitophagy, and in promoting axonal degeneration. The use of mouse and Drosophila models has significantly enhanced our understanding of MORN4's functions in these specific disease-relevant biological processes, providing potential novel targets for improving myocardial ischemia tolerance and treating axonopathies [1,4].