Polycystin-1 regulates cardiomyocyte mitophagy.

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Cellular Signaling

Background:

• Polycystin-1 (PC1) is a transmembrane protein implicated in mitochondrial damage in kidney disease.
• Its role in cardiomyocyte mitochondria remains largely uncharacterized.
• PC1 alterations are linked to mitochondrial dysfunction and disease.

Purpose of the Study:

• To investigate the regulatory role of PC1 in cardiomyocyte mitochondrial morphology and function.
• To elucidate the signaling pathways involved in PC1-mediated mitochondrial regulation.

Main Methods:

• Transmission electron microscopy of cardiomyocytes from heterozygous PC1 mice (PDK1+/-).
• PC1 knockdown in cultured rat and human iPSC-derived cardiomyocytes using siRNA.
• Assessment of mitochondrial function (membrane potential, respiration, ATP production).
• Analysis of mitophagy markers (LC3B, Parkin) and AKT-FoxO1 signaling pathway.

Main Results:

• PC1 deficiency in cardiomyocytes leads to smaller, denser, more circular mitochondria, indicative of mitochondrial fission.
• PC1 knockdown reduces OXPHOS protein levels, mitochondrial membrane potential, respiration, and ATP production.
• Mitochondrial dysfunction triggers mitophagy and disrupts mitochondrial network connectivity.
• PC1 silencing deregulates the AKT-FoxO1 signaling pathway, impacting mitochondrial metabolism and quality control.

Conclusions:

• PC1 plays a crucial role in maintaining cardiomyocyte mitochondrial morphology and function.
• PC1 deficiency induces mitochondrial fission, dysfunction, and mitophagy via the AKT-FoxO1 pathway.
• These findings offer new insights into PC1's control over cardiomyocyte mitochondria.