This preprint investigates presenilin 1 (PS1), the protein most commonly mutated in familial Alzheimer's disease, and finds that its role extends well beyond amyloid production. Using genetically engineered HEK293 cells lacking PS1, the researchers showed that a portion of the protein resides within the mitochondrial inner membrane, where it appears to help organize the structures that maintain cristae architecture. Cells lacking PS1 produced less ATP, exhibited impaired mitochondrial respiration, accumulated excess reactive oxygen species, and showed disrupted calcium handling.

The most striking findings involved mitochondrial structure. Loss of PS1 caused swollen, disorganized cristae, reduced cristae density, mitochondrial vacuolization, expansion of mitochondria-associated membranes (MAMs), and instability of mitochondrial DNA. The researchers traced many of these changes to abnormal behavior of ATAD3A, a protein involved in maintaining cristae junctions and mitochondrial organization. Without PS1, ATAD3A levels increased, oligomerized, and formed abnormal interactions with key cristae-organizing proteins including MIC60, MIC19, and OPA1.

The authors propose that PS1 functions as a structural regulator of the mitochondrial inner membrane, helping coordinate the protein networks that shape cristae and maintain mitochondrial integrity. While Alzheimer's research has traditionally focused on amyloid plaques and γ-secretase activity, these findings support the view that mitochondrial dysfunction may be a fundamental component of disease progression. If confirmed in neurons and human disease models, the work would strengthen the link between Alzheimer's disease and the breakdown of mitochondrial structure, bioenergetics, calcium regulation, and oxidative stress.