Details

Autor(en) / Beteiligte

• Patel, Akshar
• Pietromicca, Julia G.
• Venkatesan, Manigandan
• Maity, Soumya
• Bard, Jonathan E.
• Madesh, Muniswamy
• Alevriadou, B. Rita

Titel

Modulation of the mitochondrial Ca2+ uniporter complex subunit expression by different shear stress patterns in vascular endothelial cells

Ist Teil von

• Physiological reports, 2023-02, Vol.11 (3), p.e15588-n/a

Ort / Verlag

Oxford: John Wiley & Sons, Inc

Erscheinungsjahr

2023

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Mitochondrial calcium (mCa2+) uptake occurs via the Mitochondrial Ca2+ Uniporter (MCU) complex and plays a critical role in mitochondrial dynamics, mitophagy, and apoptosis. MCU complex activity is in part modulated by the expression of its regulatory subunits. Cardiovascular disease models demonstrated altered gene/protein expression of one or multiple subunits in different cells, including vascular endothelial cells (ECs). MCU complex activity was found necessary for stable flow (s‐flow)‐induced mitophagy and promotion of an atheroprotective EC phenotype. Disturbed flow (d‐flow) is known to lead to an atheroprone phenotype. Despite the role of MCU in flow‐regulated EC function, flow‐induced alterations in MCU complex subunit expression are currently unknown. We exposed cultured human ECs to atheroprotective (steady shear stress, SS) or atheroprone flow (oscillatory shear stress, OS) and measured mRNA and protein levels of the MCU complex members. SS and OS differentially modulated subunit expression at gene/protein levels. Protein expression changes of the core MCU, mCa2+ uptake 1 (MICU1) and MCU regulator 1 (MCUR1) subunits in SS‐ and OS‐exposed, compared to static, ECs suggested an enhanced mCa2+ influx under each flow and a potential contribution to EC dysfunction under OS. In silico analysis of a single‐cell RNA‐sequencing dataset was employed to extract transcript values of MCU subunits in mouse carotid ECs from regions exposed to s‐flow or d‐flow. Mcu and Mcur1 genes showed significant differences in expression after prolonged exposure to each flow. The differential expression of MCU complex subunits indicated a tight regulation of the complex activity under physiological and pathological hemodynamic conditions. Patel et al. demonstrated that flow patterns differentially modulate the Mitochondrial Ca2+ Uniporter (MCU) subunit expression at the gene and protein levels. Protein expression changes of the core MCU, mitochondrial Ca2+ uptake 1 (MICU1) and MCU regulator 1 (MCUR1) subunits in atheroprotective flow‐exposed and atheroprone flow‐exposed, compared to static, ECs suggested an enhanced mitochondrial Ca2+ influx under each flow and a potential contribution to EC dysfunction under atheroprone flow. For in vivo evidence of mechanoregulation of the MCU subunit gene expression, in silico analysis of a single‐cell RNA‐sequencing dataset was employed to extract transcript values of MCU subunits in mouse carotid ECs from regions exposed to atheroprotective versus atheroprone flow.