Mitochondrial ubiquitin ligase alleviates Alzheimer's disease pathology via blocking the toxic amyloid-β oligomer generation

Mitochondrial pathophysiology is implicated in the development of Alzheimer's disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related A beta pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of A beta fibrils, but not the spontaneous formation of A beta fibrils and plaques, leading to excessive secondary generation of toxic and dispersible A beta oligomers. Consistent with this, MITOL-deficient mice with A beta etiology exhibited worsening cognitive decline depending on A beta oligomers rather than A beta plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of A beta form, oligomers or plaques, responsible for disease development. Takeda et al. investigate the role of mitochondrial ubiquitin ligase (MITOL) in Alzheimer's disease progression. They demonstrate that MITOL has a direct effect on mitochondrial dynamics and functioning and its ablation can enhance the seeding effect of A beta -plaques, leading to cognitive decline in the transgenic mice model of Alzheimer's disease.

Automated summary

The loss of MITOL exacerbates cognitive decline in AD mouse models by promoting the accumulation of Aβ oligomers, rather than Aβ plaques, suggesting that alteration in mitochondrial morphology plays a key role in Alzheimer's disease progression.