The Mitochondrial Ca²⁺ import complex is altered in ADPKD.

Area of Science:

• Cell Biology
• Nephrology
• Mitochondrial Biology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) arises from mutations in PKD1 or PKD2, leading to renal cyst formation and dysfunction.
• Mitochondria play a crucial role in cellular calcium (Ca²⁺) signaling and metabolism, processes significantly altered in ADPKD.
• Understanding the mitochondrial Ca²⁺ uptake complex's role in ADPKD pathogenesis is critical for identifying therapeutic strategies.

Purpose of the Study:

• To investigate the function of the mitochondrial Ca²⁺ uptake complex in polycystin-1 (PC1)-deficient cells relevant to ADPKD.
• To determine the impact of altered mitochondrial Ca²⁺ handling on cystogenesis and cellular processes in ADPKD models.

Main Methods:

• Analysis of mitochondrial Ca²⁺ uniporter (MCU) and voltage-dependent anion channels (VDAC) expression in ADPKD models.
• Measurement of Ca²⁺ release from the endoplasmic reticulum (ER) and mitochondrial Ca²⁺ uptake using fluorescent dyes.
• Assessment of cyst growth, apoptosis, and cell proliferation following inhibition of mitochondrial Ca²⁺ uptake with Ru360.
• Evaluation of the effect of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-809 on mitochondrial function and Ca²⁺ signaling.

Main Results:

• Down-regulation of MCU, VDAC, and pyruvate dehydrogenase phosphatase (PDHX) was observed in ADPKD models.
• PC1-null cells exhibited increased ER Ca²⁺ release and enhanced mitochondrial Ca²⁺ uptake.
• Inhibition of mitochondrial Ca²⁺ uptake significantly reduced cyst growth, apoptosis, and cell proliferation.
• Treatment with VX-809 reversed mitochondrial protein deficits and normalized aberrant Ca²⁺ signaling.

Conclusions:

• Aberrant ER Ca²⁺ release and altered mitochondrial Ca²⁺ uptake are key features of PC1 malfunction in ADPKD.
• Mitochondrial Ca²⁺ uptake is a critical regulator of cyst growth and cellular dynamics in ADPKD.
• Targeting mitochondrial Ca²⁺ signaling presents a promising therapeutic avenue for ADPKD, with potential for reversal by CFTR modulators.