Presenilin 1 is located at mitochondrial inner membrane and regulates mitochondrial crista junction protein arrangement and crista formation in HEK293 cells

Presenilin 1 (PS1), a key pathogenic factor in familial Alzheimer’s disease, is implicated in the regulation of mitochondrial functions, yet its precise sub-mitochondrial localization and underlying mechanisms remain poorly understood. In this study, we generated PS1 knockout cell lines to investigate the role of PS1 in mitochondrial structure and function. Our results demonstrated that PS1 is directly localized to the mitochondrial inner membrane. PS1 deficiency led to reduced ATP production, impaired mitochondrial respiration capacity, decreased mitochondrial membrane potential, disrupted Ca2+ homeostasis, and elevated ROS accumulation. Moreover, loss of PS1 caused abnormal mitochondrial crista structure. Further analysis revealed that PS1 interacts with mitochondrial inner membrane proteins. Its absence promotes ATAD3A oligomerization and disrupts its arrangement at mitochondrial crista junctions, leading to expansion of the mitochondria-associated membrane and instability of mitochondrial DNA. Our findings demonstrate that PS1 acts as a central regulator of mitochondrial crista morphogenesis by modulating protein interaction networks at crista junctions, thereby illuminating fundamental molecular mechanisms contributing to mitochondrial dysfunction in Alzheimer’s disease.