Cystathionine beta synthase regulates mitochondrial dynamics and function in endothelial cells

Area of Science:

• Endothelial cell biology
• Mitochondrial function and dynamics
• Cardiovascular and neurovascular disease mechanisms

Background:

• Mutations in the human cystathionine beta synthase (CBS) gene are linked to endothelial dysfunction, contributing to cardiovascular and neurovascular diseases.
• CBS is the primary enzyme producing hydrogen sulfide (H2S) in endothelial cells (ECs), and H2S has known roles in attenuating reactive oxygen species (ROS) and improving mitochondrial function.

Purpose of the Study:

• To investigate whether impaired CBS/H2S activity could lead to mitochondrial dysfunction through alterations in mitochondrial dynamics within ECs.
• To elucidate the molecular mechanisms linking CBS deficiency, mitochondrial dysfunction, and endothelial cell pathology.

Main Methods:

• Silencing of the CBS gene in endothelial cells.
• Assessment of mitochondrial morphology (fragmentation/fusion), oxidative phosphorylation efficiency, and ROS production.
• Analysis of mitofusin 2 (MFN2) expression and endoplasmic reticulum-mitochondria contacts.
• Evaluation of mitophagy and EC death.
• Rescue experiments using H2S donors.

Main Results:

• CBS silencing resulted in mitochondria fragmentation, reduced oxidative phosphorylation, and impaired EC function.
• CBS deficiency led to increased ROS production, decreased MFN2 expression, disrupted ER-mitochondria contacts, enhanced mitochondrial fission, and increased mitophagy and EC death.
• Treatment with H2S donors significantly rescued these observed defects.

Conclusions:

• CBS deficiency disrupts mitochondrial function and ER-mitochondria tethering in ECs, primarily through elevated ROS and altered mitochondrial dynamics.
• The CBS/H2S signaling pathway is crucial for maintaining mitochondrial integrity and EC function.
• Targeting the CBS/H2S axis presents a potential therapeutic avenue for endothelial dysfunction-related diseases.