Mitochondrial pathophysiology is implicated in Alzheimer's disease (AD). This study finds that MITOL/MARCH5, a mitochondrial ubiquitin ligase regulating mitochondrial dynamics, is downregulated in AD patients. MITOL deletion in an AD mouse model exacerbated cognitive decline and mitochondrial impairments. This was linked to increased production of toxic Aβ oligomers due to enhanced seeding by Aβ fibrils, rather than increased Aβ plaque formation. The findings suggest that mitochondrial morphology alterations direct Aβ aggregation towards oligomers, a key factor in AD pathogenesis.
