P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers

Area of Science:

• Mitochondrial biology
• Metabolic disease research
• Cellular signaling pathways

Background:

• Mitochondrial dysfunction is a key driver of metabolic dysfunction-associated steatohepatitis (MASH).
• The Shc protein family, particularly the p46Shc isoform, is implicated in aging-related MASH progression.
• The in vivo role of p46Shc in regulating lipid metabolism and mitochondrial function in MASH remains unclear.

Purpose of the Study:

• To investigate the in vivo metabolic consequences of p46Shc induction in the liver.
• To determine the impact of p46Shc on mitochondrial function, lipid β-oxidation, and oxidative stress in a mouse model of aging and MASH.
• To explore the therapeutic potential of targeting p46Shc in MASH.

Main Methods:

• Generation of p46Shc-inducible mice and aging studies.
• Dietary interventions including chow and high-fat, high-fructose (fast-food) diets.
• Assessment of liver injury, inflammation, lipid peroxidation, mitochondrial morphology (electron microscopy), oxygen consumption (Oroboros), β-hydroxybutyrate production, and reactive oxygen species (ROS) generation.
• Evaluation of dominant-negative p46Shc effects on ACAA2 activity and β-oxidation.

Main Results:

• p46Shc induction exacerbated liver injury, inflammation, and lipid peroxidation in aged mice, particularly on a fast-food diet.
• Mitochondria displayed swelling and aberrant cristae, with reduced oxygen consumption and suppressed β-hydroxybutyrate production.
• Increased ROS production was observed, while dominant-negative p46Shc expression improved β-oxidation and reduced oxidative stress.
• p46Shc overexpression did not significantly alter liver triglyceride levels.

Conclusions:

• p46Shc induction in aging represses acetyl-coenzyme A acyltransferase 2 (ACAA2), leading to decreased mitochondrial β-oxidation and increased lipid peroxidation.
• Maintaining mitochondrial β-oxidation and ketogenesis is crucial for preventing liver injury in MASH.
• Targeting Shc-mediated maladaptive responses presents a promising therapeutic strategy for aging-related MASH.