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Liver Disease Reveals KIF12 as a Critical Regulator of Mitochondria, Lysosome and Cilia Localization
Insights
Kinesin family member 12 (KIF12) mutations cause pediatric liver disease. This study reveals KIF12 dysfunction disrupts organelle positioning in human bile duct cells, offering insights into cholestatic liver disease mechanisms.
Area of Science:
- Cell Biology
- Genetics
- Hepatology
Background:
- Pathogenic variants in KIF12 are linked to pediatric liver disease.
- The cellular mechanisms driving KIF12-related liver pathology are not well understood.
- KIF12 is a kinesin motor protein crucial for intracellular transport.
Purpose of the Study:
- To investigate the cellular role of KIF12 in human cholangiocytes.
- To elucidate the mechanisms by which KIF12 mutations lead to liver disease.
- To explore KIF12's function in organelle dynamics and primary cilia.
Main Methods:
- Single-cell RNA sequencing to determine KIF12 expression in the liver.
- Generation of KIF12-mutant induced pluripotent stem cells (iPSCs) differentiated into cholangiocyte-like cells (iCCs) and organoids.
- Single-molecule fluorescence microscopy to observe KIF12 localization and dynamics.
- Assessment of organelle positioning (mitochondria, lysosomes) and primary cilia in iCCs.
Main Results:
- KIF12 is predominantly expressed in human biliary epithelial cells.
- KIF12 dysfunction in iCCs leads to abnormal perinuclear clustering of mitochondria and lysosomes.
- Mutant KIF12 causes mislocalization of primary cilia in cholangiocytes.
- Restoring wildtype KIF12 expression corrected organelle positioning and normalized GGT activity.
Conclusions:
- KIF12 plays a critical role in maintaining organelle positioning and primary cilia function in human cholangiocytes.
- KIF12 dysfunction disrupts cellular homeostasis, contributing to cholestatic liver disease pathogenesis.
- This study highlights a novel link between kinesin motor proteins, organelle dynamics, and liver disease, opening avenues for genetic therapies.
Abstract:
Pathogenic variants in kinesin family member 12 (KIF12) cause pediatric liver disease, yet the cellular mechanisms underlying this phenotype remain unknown. Here we show that KIF12 expression in the healthy human liver is primarily detected in biliary epithelial cells, as revealed by single cell RNA-sequencing data. To investigate its role in biliary pathology, we introduced a homozygous KIF12 p.Arg219* mutation into induced pluripotent stem cells (iPSCs), which were differentiated into 2D cholangiocyte-like cells (iCCs) and 3D biliary organoids. Pioneering single-molecule fluorescence microscopy in live iCCs, we observed wildtype KIF12 co-localizing with microtubules, consistent with its predicted role as a microtubule-associated motor protein. Our data reveals that KIF12 dysfunction causes abnormal perinuclear clustering of mitochondria and lysosomes, and mislocalization of primary cilia in cholangiocytes. Restoration of wildtype KIF12 expression in mutant KIF12 iCCs rescued organelle positioning and normalized GGT activity. This study uncovers a novel link between KIF12 dysfunction and organelle dynamics in human cholangiocytes, extending our understanding of kinesin roles beyond their established functions in neuronal systems. Our findings provide new insights into the pathogenesis of KIF12-related cholestatic liver disease and lay the groundwork for developing targeted genetic therapies.
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