Functional compartmentalization of hepatic mitochondrial subpopulations during MASH progression

Area of Science:

• Hepatology
• Mitochondrial Biology
• Metabolic Diseases

Background:

• The function of peridroplet mitochondria (PDM) in liver disease, particularly metabolic dysfunction-associated steatohepatitis (MASH), is not well understood.
• Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to MASH, a condition characterized by inflammation and liver damage.

Purpose of the Study:

• To investigate the distinct roles and functions of hepatic cytoplasmic mitochondria (CM) and PDM in the progression of MASLD to MASH.
• To characterize the bioenergetic and structural differences between CM and PDM in healthy and diseased liver states.

Main Methods:

• Isolation of hepatic CM and PDM from a mouse model of diet-induced MASLD/MASH and control mice.
• Proteomics analysis to determine compositional and functional differences between mitochondrial populations.
• Assessment of mitochondrial respiration, oxidative phosphorylation (OXPHOS) protein levels, TCA cycle flux, and fatty acid oxidation capacity.
• Transmission electron microscopy (TEM) to evaluate mitochondrial morphology and dynamics (MFN2 and DRP1 protein levels).

Main Results:

• An inverse relationship was observed between hepatic CM and PDM levels during the progression from healthy liver to steatosis and advanced MASH.
• PDM demonstrated higher bioenergetic activity, pyruvate oxidation capacity, and OXPHOS protein levels compared to CM.
• CM exhibited increased fatty acid oxidation capacity as MASH progressed.
• Mitochondrial morphology changed from larger and elongated in healthy/early steatosis to small and fragmented in advanced MASH, correlating with MFN2 (PDM) and DRP1 (CM) levels.

Conclusions:

• Hepatic PDM and CM are compositionally and functionally distinct mitochondrial populations.
• PDM are primarily involved in energy production via pyruvate oxidation and OXPHOS, while CM are more involved in fatty acid oxidation, especially during MASH progression.
• Distinct roles of CM and PDM highlight their differential involvement in the pathogenesis of MASLD and MASH.