Exploring multiorgan mitochondrial dysfunction in the switch toward progressive MASLD in AMLN mice

Area of Science:

• Cell Biology
• Metabolic Diseases
• Mitochondrial Medicine

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) involves hepatic mitochondrial issues.
• The impact of mitochondrial alterations on other organs during MASLD progression remains unclear.

Purpose of the Study:

• To investigate mitochondrial morphology, function, and mitophagy in liver and non-liver tissues during MASLD progression.
• To assess the correlation between tissue mitochondrial impairment and circulating cell-free mitochondrial DNA.

Main Methods:

• Utilized a C57Bl/6 mouse model fed an AMLN diet to mimic the human MASLD spectrum.
• Employed Transmission Electron Microscopy (TEM) to evaluate mitochondrial morphology in liver tissues.
• Assessed mitophagy pathway, mitochondrial complex activities, OXPHOS protein levels, ATP production, and circulating cell-free mitochondrial DNA.

Main Results:

• Progressive mitochondrial swelling and cristae disorganization were observed in the liver from MASLD to MASH-fibrosis stages.
• Mitophagy pathway was reduced in MASH-fibrosis, leading to damaged mitochondria accumulation.
• Mitochondrial complex activities, OXPHOS protein levels, and ATP production were decreased across liver, adipose, muscle, and cardiac tissues.
• Elevated cell-free circulating mitochondrial DNA levels correlated with tissue mitochondrial impairment.

Conclusions:

• Mitochondrial dysfunction, including morphological changes and impaired activity, is a hallmark of MASLD progression in the liver.
• Mitochondrial alterations extend beyond the liver, affecting adipose tissue, muscle, and heart.
• Circulating cell-free mitochondrial DNA serves as a biomarker for systemic mitochondrial damage in MASLD.