Non-apoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans

Abstract While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans , promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the mechanistic role of BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health. Significance statement BH3-only proteins were known for their function in inducing cell death. Their presence in healthy adult neurons, however, suggests additional roles. Our study focused on the BH3-only protein EGL-1 in the nematode Caenorhabditis elegans , where its apoptotic role was discovered. We reveal a new role in cell-autonomously promoting exopher production – a process where neurons extrude large vesicles containing potentially harmful cell contents. EGL-1 appears to promote this by regulating mitochondrial dynamics. We also report that low levels of EGL-1 benefit neuronal health and function. These findings expand our understanding of BH3-only proteins, mitochondrial dynamics, and exopher production in neurons and provide insights for neurodegenerative diseases.