MFN2-mediated decrease in mitochondria-associated endoplasmic reticulum membranes contributes to sunitinib-induced...

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Endothelial Cell Function

Background:

• Tyrosine kinase inhibitors (TKIs) are crucial in cancer therapy but frequently induce hypertension.
• The precise mechanisms underlying TKI-induced hypertension, particularly the role of endothelial cell mitochondria, remain incompletely understood.

Purpose of the Study:

• To investigate the role of mitochondrial morphology and function, specifically mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.
• To elucidate the molecular pathways involved in sunitinib's effects on endothelial cells.

Main Methods:

• In vitro and in vivo experiments assessed reactive oxygen species (ROS), nitric oxide (NO), vasorelaxation, blood pressure, and mitochondrial function in endothelial cells.
• Mitochondrial morphology, MAMs, and key protein expressions (Akt, MFN2, IP3R1) were analyzed under sunitinib treatment.

Main Results:

• Sunitinib triggered mitochondrial dysfunction, increased ROS, reduced ATP and NO signaling, and decreased mitochondrial calcium levels in endothelial cells.
• Sunitinib exposure led to mitochondrial elongation and reduced MAMs, which were reversed by reinforcing MAMs using an adeno-virus linker.
• Augmenting MAMs expression mitigated sunitinib-induced hypertension in mice by restoring endothelium-dependent relaxation.

Conclusions:

• Sunitinib induces endothelial dysfunction and hypertension via mitochondrial dysfunction, Akt/MFN2-mediated reduction in MAMs, and IP3R1 dephosphorylation.
• Targeting MAMs integrity and related molecular pathways presents a potential therapeutic strategy for managing TKI-induced hypertension.