iPSC-Derived Hepatocytes from Patients with MASLD Exhibit Early Mitochondrial Dysfunction

Area of Science:

• Hepatology
• Mitochondrial Biology
• Stem Cell Research

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by impaired hepatocyte mitochondrial adaptation to lipids.
• Mitochondrial dysfunction in MASLD contributes to reactive oxygen species (ROS) production and disease progression.
• Investigating mitochondrial function in patient-derived cells offers insights into early disease mechanisms.

Purpose of the Study:

• To determine if induced pluripotent stem cells (iPSCs) from MASLD patients, differentiated into hepatocyte-like cells (iPSC-Heps), display mitochondrial dysfunction.
• To assess lipid accumulation, mitochondrial function, and cellular energy status in MASLD iPSC-Heps.
• To explore the role of PNPLA3 genotype in MASLD-associated mitochondrial alterations.

Main Methods:

• Differentiated iPSCs from 10 MASLD patients and 10 healthy controls into iPSC-Heps.
• Assessed mitochondrial mass and function under basal and palmitate-challenged conditions.
• Measured gene expression, oxygen consumption, ROS production, and ATP levels.

Main Results:

• MASLD iPSC-Heps accumulated more lipids than controls.
• Mitochondrial content was similar, but MASLD iPSC-Heps showed reduced oxygen consumption with palmitate.
• MASLD iPSC-Heps exhibited increased ROS production and decreased ATP levels post-palmitate treatment.
• These mitochondrial differences were independent of PNPLA3 genotype.

Conclusions:

• MASLD patient-derived iPSC-Heps recapitulate mitochondrial dysfunction observed in early MASLD.
• The observed mitochondrial alterations precede the progression to steatohepatitis.
• Mitochondrial dysfunction in this model is not solely dependent on the PNPLA3 genotype.