Presenilin 1 is located in the mitochondrial inner inner membrane and regulates mitochondrial cristae junction protein arrangement and cristae 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 generate PS1-knockout cell lines to investigate the role of PS1 in mitochondrial structure and function. Our results indicate that PS1 is directly localized in the mitochondrial inner membrane. PS1 deficiency leads to reduced ATP production, impaired mitochondrial respiration capacity, decreased mitochondrial membrane potential, disrupted Ca 2+ homeostasis, and elevated ROS accumulation. Moreover, loss of PS1 leads to abnormal mitochondrial cristae structure. Further analysis reveals that PS1 interacts with mitochondrial inner membrane proteins. Its absence promotes ATAD3A oligomerization and disrupts its arrangement at mitochondrial cristae 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 cristae morphogenesis by modulating protein interaction networks at cristae junctions, thereby illuminating fundamental molecular mechanisms contributing to mitochondrial dysfunction in Alzheimer's disease.