Bok, also known as Bcl-2-related ovarian killer, is a member of the Bcl-2 family. Based on sequence and structural similarities to BAX and BAK, it was initially classified as a pro-apoptotic protein. However, its actual functions are complex and controversial, involving not only apoptosis-related pathways but also non-apoptotic roles such as regulating endoplasmic reticulum/mitochondria contact sites, mitochondrial dynamics, mitophagy, ER proteostasis, and the unfolded protein response [1,3,4,5,6,7].

In APPswe/PS1dE9 (APP/PS1) mice, neuron-specific loss of Bok is associated with mitochondrial damage and mitophagy defects. Overexpressing bok in hippocampal neurons of APP/PS1 mice alleviates mitophagy and mitochondrial malfunction, improving cognitive function, while knockdown worsens Alzheimer's disease-related changes, indicating Bok's role in Alzheimer's disease through regulating Parkin-mediated mitophagy [2]. In murine embryonic fibroblasts, Bok deficiency leads to decreased proximity of the ER to the mitochondria, altered protein composition of mitochondria-associated membranes, and disrupted calcium transfer from the ER to the mitochondria, affecting apoptosis [6]. In neurons, BOK-deficient cells have an attenuated response to ER stress in all three signaling branches of the unfolded protein response, suggesting a role in protecting ER proteostasis [7]. In HeLa cells, Bok knockout causes mitochondrial fragmentation, and overexpression leads to apoptosis. Proximity labeling shows Bok is proximal to proteins involved in mitochondrial fission, endoplasmic reticulum-plasma membrane junctions, and among Bcl-2 family members, only Mcl-1 [8].

In conclusion, Bok has diverse biological functions. Through studies using gene knockout models in mouse models and cell lines, Bok has been shown to play important roles in apoptosis, mitophagy, mitochondrial function, ER proteostasis, and is potentially relevant to Alzheimer's disease. These model-based research findings help to better understand Bok's functions and its potential as a therapeutic target in related diseases.