Esyt1, or Extended Synaptotagmin 1, is a Ca²⁺ -dependent mediator involved in endoplasmic reticulum (ER)-plasma membrane bridge formation [2,4]. It plays a role in multiple biological processes such as maintaining mitochondrial lipid and calcium homeostasis, regulating GPR133 signaling, and participating in lipid metabolism. It also contributes to synaptic function and growth, and is associated with various pathways like store-operated calcium entry (SOCE) [1,2,4,5]. Genetic models are valuable for studying its functions in different physiological and pathological conditions.

In gene knockout studies, deletion of Esyt1 reduced the number and length of mitochondria-ER contact sites (MERCs), impaired ER to mitochondria calcium flux, and altered the mitochondrial lipidome, indicating its role in mitochondrial and cellular homeostasis [1]. In glioblastoma, Esyt1 knockdown or knockout increased GPR133 signaling and slowed tumor growth, suggesting its tumorigenic functions [2]. In a mouse model of ALS, down-regulation of Esyt1 in V1 interneurons led to loss of connectivity with motor neurons, while V1-restricted overexpression of Esyt1 rescued inhibitory synapses, increased motor neuron survival, and ameliorated motor phenotypes [3].

In conclusion, Esyt1 is essential for maintaining mitochondrial homeostasis, regulating G-protein coupled receptor signaling, and stabilizing neuron-neuron connectivity. Gene knockout mouse models have revealed its significant roles in diseases such as glioblastoma and ALS, highlighting its potential as a therapeutic target in these disease areas.