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MFN2-mediated decrease in mitochondria-associated endoplasmic reticulum membranes contributes to sunitinib-induced
Yao Qu1, Zhi-Xue Liu2, Xiao-Xu Zheng2
1Department of Cardiology, Harbin Medical University Cancer Hospital, NHC Key Laboratory of Cell Transplantation, Department of Cardiology, Central Laboratory, The First Affiliated Hospital of Harbin Medical University, Institute of Metabolic Disease, Heilongjiang Academy of Medical Sciences, Heilongjiang Key Laboratory for Metabolic Disorder & Cancer Related Cardiovascular Diseases, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China; Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA.
Abstract:
Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.
Methods:
Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition.
Results:
Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca2+]M) levels, and impaired endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) signaling in HUVECs. In addition, sunitinib also decreased mitochondrial membrane potential, elongated mitochondria, and reduced MAMs. Remarkably, these effects were reversed by an adeno-virus linker (Ad-linker) that reinforces MAMs. Engineered augmentation of MAMs using AAV-FLT1-linker significantly mitigated sunitinib-induced hypertension, by restoring endothelium-dependent relaxation in mice, highlighting the crucial role of MAMs in this process. Further analyses revealed that sunitinib enhanced Akt-mediated expression of mitofusin 2 (MFN2), causing mitochondrial elongation, and induced dephosphorylation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) at residues Y1737/Y1738, reducing [Ca2+]M. Our study suggests that increased MFN2 expression and IP3R1 dephosphorylation are critical in sunitinib-induced MAMs reduction and [Ca2+]M homeostasis.
Conclusion:
Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IP3R1 dephosphorylation in endothelial cells, leading to endothelial dysfunction and hypertension. Our results provide the potential therapeutic targets for combating TKI-induced hypertension.
Insights
Tyrosine kinase inhibitors like sunitinib cause hypertension by impairing endothelial cell mitochondria and reducing mitochondria-associated endoplasmic reticulum membranes (MAMs). Restoring MAMs function may offer a therapeutic strategy against this side effect.
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.
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