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MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress
Shun Nagashima1, Keisuke Takeda1, Nobuhiko Ohno2
1Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Abstract:
Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.
Insights
Mitochondrial dysfunction, caused by the loss of MITOL, triggers neuroinflammation and abnormal brain activity. This suggests a link between mitochondrial issues and inflammatory brain diseases like psychiatric disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial abnormalities are linked to developmental disorders, but causality is unclear.
- Neuroinflammation, involving astrogliosis and microglial activation, is implicated in brain disorders.
Purpose of the Study:
- To investigate the role of mitochondrial ubiquitin ligase MITOL in neuronal mitochondrial structure and function.
- To explore the impact of MITOL deficiency on ER-mitochondria tethering and subsequent neuroinflammation.
Main Methods:
- Utilized in vivo studies to characterize three-dimensional mitochondrial structures in MITOL-deficient neurons.
- Assessed oxidative stress levels, astrogliosis, microglial activation, and behavioral changes.
Main Results:
- Deletion of MITOL significantly reduced ER-mitochondria contact sites and impaired cardiolipin biogenesis.
- MITOL deficiency led to abnormal mitochondrial morphology, characterized by reduced branching and increased fission.
- Enhanced oxidative stress in the brain resulted in astrogliosis, microglial activation, and abnormal behavior.
Conclusions:
- Reduced ER-mitochondria tethering and excessive mitochondrial fission due to MITOL loss contribute to neuroinflammation via oxidative stress.
- Mitochondrial abnormalities may increase the risk for inflammatory brain diseases, including psychiatric disorders.
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