Abstract: SA-PO0135
Spatial Transcriptomics Identifies Mitochondria-Driven Cystogenic Signature in PKD/Polycystic Liver Disease and Its Suppression After Targeting Mitochondrial Function
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Masyuk, Tetyana V., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Masyuk, Anatoliy, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Trussoni, Christy, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Milko, Anastasiia, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Sherman, Will A., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Krivonos, Alexandra, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Torres, Vicente E., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Irazabal, Maria V., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Miller, Thomas R., ICM Therapeutics, Las Vegas, Nevada, United States
- Coutts, Stephen M., ICM Therapeutics, Las Vegas, Nevada, United States
- LaRusso, Nicholas F., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Hogan, Marie C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Polycystic kidney (PKD) & liver diseases (PLD) are genetic disorders with substantial morbidity. While there are limited therapies for PKD or PLD alone, concurrent treatment of these co-existing diseases is elusive. Recently, mitochondrial dysfunction (MT-DY) has emerged as a PKD hallmark. We previously showed enhanced mitochondrial pathways (MT-PW) in human kidneys/livers, with enrichment scores (ENCR) for mitochondrion cluster of 12.8 & 5.6, respectively (ASN 2025, FR-PO0685). Here, we tested whether MT-DY targeting with ICM-926, a novel compound that modulates mitochondrial functions, affects cyst progression & spatial transcriptomic landscape in PCK rats.
Methods
Spatial transcriptomics analysis (STA) & functional clustering were performed on livers/ kidneys of wild-type (WT), & untreated & ICM-treated PCK rats (age- & sex-matched; n=3 per group) to identify affected cellular pathways. Mitochondrial morphology was analyzed in human & rat liver tissue by transmission electron microscopy (TEM). Rats (n=20) were treated with ICM x 6 wks. Kidney & liver cystogenesis were assessed (CystAnalyser®), & treatment-associated changes in mitochondria-related differentially expressed genes (MT-DEGs) examined.
Results
Consistent with observations in human tissues, mitochondrion was enriched in livers /kidneys of PCK rats (ENCR 6.7 and 5.6, respectively). In livers, TEM revealed swollen, rounded mitochondria with loss of internal cristae structure & damaged membrane. We identified 38 MT-DEGs among 612 total DEGs in kidneys, & 68 MT-DEGs among 877 total DEGs in livers of untreated PCK- rats. The most highly enriched components included mitochondrion, inner mitochondrial membrane & matrix, & respiratory chain complex. ICM-926 reduced cystic index, diameter & number by ~35–50%. After treatment, MT-DEGs in kidneys/livers decreased by ~25%; mitochondrial enrichment was moderated, whereas immune processes & extracellular matrix organization became strongly enriched.
Conclusion
STA shows strong enrichment of MT-PW in untreated PCK rats, suggesting a highly oxidative, mitochondria-dense metabolic program that supports an energy-active proliferative state in kidney/liver. ICM decreased kidney/liver cyst burden by reducing a mitochondria-driven cystogenic signature. We identified shared MT-PW in kidneys & livers, suggesting a unified systemic therapeutic response.
Funding
- Commercial Support – ICM Therapeutics