Loss of the mitochondrial protein mitoNEET in mice is associated with cognitive impairments and increased neuroinflammation

Background: Mitochondrial dysfunction is implicated in several neurodegenerative diseases associated with memory and cognitive deficits, including Alzheimer's disease. Changes in bioenergetic function results in reactive oxygen species, oxidative damage and consequently neuroinflammation, which contributes to neuronal cell loss.

Objective: In this study, we evaluated the impact of the loss of the redox active [2Fe-2S] mitochondrial-associated protein mitoNEET (CISD1) on neuroinflammation and cognition using an age-appropriate preclinical model. While associations between neuroinflammation and poor cognitive impacts have been shown in recent work, little has been done to assess whether loss of mitoNEET is associated with changes in neuroinflammatory markers or negative cognitive-behavioral outcomes.

Methods: Using 9-11-month-old mitoNEET knockout (CISD1-/-) and wild-type mice, we conducted a battery of cognitive tests to assess the impact of mitoNEET loss on performance. We then histologically evaluated the effect of absence of mitoNEET on markers of neuroinflammation in the aged brain.

Results: We found loss of mitoNEET in mice was associated with a significant reduction in willingness to explore within an open field and impaired short-term spatial working memory in the Y-maze. We also found a significant reduction in novel object recognition memory that was gene-dependent and accompanied by reduced c-fos expression in hippocampus and cortical regions.

Conclusions: Our findings indicate that mitoNEET loss is significantly associated with impairments in cognitive-behavioral and neuroinflammatory outcomes; specifically, learning and memory, anxiety-like behaviors, neuroinflammation, and neural activation. This is the first study to demonstrate cognitive-associated behavioral deficits with neuroinflammation in the mitoNEET knockout mouse model.