New evidence links a failure of cellular cleanup to the distinctive brain damage of Alzheimer’s disease. In a study in Nature Neuroscience, researchers used an in vivo mitophagy reporter mouse line to watch how mitochondria are handled inside neurons as pathology develops. Their results reveal that defective mitochondrial clearance does not simply leave cells overloaded—it can organize mismanaged organelles into a specific, previously unrecognized structure.
The team focused on AD model mice carrying human APP/PSEN1 mutations and a fluorescent mitophagy sensor (mt-Keima). This reporter shifts optical properties depending on mitochondrial conditions, allowing investigators to distinguish mitochondria residing in acidic lysosomal environments from those that remain neutral. Over time, neurons in these animals accumulated large clusters of both acidic and neutral mitochondria within neuronal processes.
These accumulations formed “mitochondrial plaques” (MPs), a pathological architecture distinct from classical amyloid deposits. The authors propose that MPs arise from two connected problems: abnormal mitochondrial buildup and a delayed attempt by the lysosomal system to recruit those organelles for degradation. In other words, the cell appears to summon lysosomes too late to prevent the formation of persistent mitochondrial masses.
Crucially, the study shows that even when lysosomes are recruited, clearance remains incomplete. Impaired lysosomal function interferes with the final steps of mitophagy, trapping mitochondria in a state of partial processing. As a result, both neutral mitochondria (not fully delivered or processed) and acidic mitochondria (attempting degradation) accumulate together inside the MPs.
The researchers also examined whether this phenomenon depends on amyloid pathology. MPs often co-developed with amyloid plaques to form mixed lesions, but the mitochondrial structures could also appear independently at early disease stages. That timing supports a causal role for mitochondrial quality-control failure rather than a purely downstream effect of amyloid deposition.
To test generality, the team detected mitochondrial plaques in the 5xFAD AD model, strengthening the link between the mechanism and AD-like genetic stress. Finally, they extended the findings to human biology by identifying corresponding MPs in postmortem Alzheimer’s disease brains, indicating that the phenomenon is not restricted to mouse models.
Together, the work establishes mitochondrial plaques as a new pathological entity and implicates lysosomal dysfunction as a key bottleneck in mitophagy during Alzheimer’s disease. By providing direct in vivo evidence of how mitochondria can organize when clearance fails, the study adds a mechanistic target for future therapeutic strategies aimed at restoring mitochondrial quality control.
Subject of Research: Alzheimer’s disease pathology; mitophagy; lysosomal dysfunction; mitochondrial accumulation.
Article Title: Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease.
Article References: Dan, X., Croteau, D.L., Liu, W. et al. Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease. Nat Neurosci (2026). https://doi.org/10.1038/s41593-026-02390-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41593-026-02390-1
Keywords: mitophagy reporter; mitochondrial plaques; lysosomal dysfunction; neuronal processes; amyloid; Alzheimer’s disease
