Mutant NOTCH3ECD Triggers Defects in Mitochondrial Function and Mitophagy in CADASIL Cell Models.

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarction and Leukoencephalopathy (CADASIL) is a genetic small-vessel brain disease.
• NOTCH3 extracellular domain (NOTCH3ECD) deposition is the primary pathology in CADASIL.
• The specific impact of NOTCH3ECD on mitochondrial function in CADASIL remains unclear.

Purpose of the Study:

• To investigate the role of mitochondrial dysfunction in CADASIL.
• To determine how NOTCH3ECD deposition affects mitochondrial structure and function.

Main Methods:

• Established human embryonic kidney-293T cell models with NOTCH3ECD alterations.
• Assessed mitochondrial function using flow cytometry and structure via transmission electron microscopy.
• Evaluated mitophagy using western blotting and immunofluorescence.

Main Results:

• NOTCH3ECD deposition altered mitochondrial morphology and function.
• NOTCH3ECD protein levels correlated with mitochondrial quality and directly bound to mitochondria.
• Autophagy and mitophagy were induced but impaired, leading to abnormal mitochondrial accumulation.

Conclusions:

• NOTCH3ECD deposition presents a common pathological feature across different NOTCH3 mutations in CADASIL.
• This study provides novel insights into NOTCH3ECD's role in mitochondrial dysfunction and mitophagy.
• Findings highlight potential therapeutic targets for CADASIL by addressing mitochondrial health.