Calciprotein particle-induced calcium overload triggers mitochondrial dysfunction in endothelial cells

Area of Science:

• Biochemistry
• Cell Biology
• Nephrology

Background:

• Calciprotein particles (CPPs) are elevated in chronic kidney disease (CKD) and linked to vascular disease.
• Mechanisms linking CPPs to vascular disease remain unclear.
• Previous work showed CPPs cause endothelial cell (EC) dysfunction via reduced nitric oxide (NO) and increased superoxide.

Purpose of the Study:

• To investigate if CPPs induce mitochondrial calcium overload in ECs.
• To determine if this overload triggers mitochondrial dysfunction and EC activation.
• To explore potential therapeutic targets for CPP-induced vascular damage.

Main Methods:

• Human umbilical vein ECs were exposed to CPPs.
• Cytosolic and mitochondrial calcium levels were measured.
• Proteome analysis assessed endoplasmic reticulum and mitochondrial function.
• Respirometry evaluated cellular respiration and mitochondrial integrity.
• Cyclosporin A was used to inhibit mitochondrial permeability transition pores.

Main Results:

• CPPs significantly increased cytosolic and mitochondrial calcium in ECs.
• Impaired endoplasmic reticulum calcium signaling and reduced mitochondrial OXPHOS proteins were observed.
• Decreased cellular respiration, mitochondrial membrane potential, and antioxidant capacity occurred.
• CPP exposure led to mitochondrial loss, EC activation, and cell death.
• Cyclosporin A attenuated CPP-induced EC activation and cell death.

Conclusions:

• CPP-induced calcium overload is a key trigger of mitochondrial dysfunction in ECs.
• This dysfunction leads to EC activation and cell loss, contributing to CKD vascular disease.
• Targeting CPP-induced mitochondrial dysfunction may preserve EC function and mitigate vascular complications in CKD.