Malic Enzyme 1 Limits Acetaminophen-Induced Liver Injury by Sustaining Redox and Bioenergetic Homeostasis

Area of Science:

• Biochemistry
• Hepatology
• Metabolic pathways

Background:

• Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI).
• N-acetylcysteine (NAC) is an effective antidote but has limitations in delayed treatment scenarios.
• Metabolic enzymes influencing NADPH levels may impact APAP hepatotoxicity severity.

Purpose of the Study:

• To investigate the role of Malic enzyme 1 (ME1) in APAP-induced liver injury (AILI).
• To elucidate the mechanisms by which ME1 affects hepatocellular vulnerability and survival following APAP overdose.

Main Methods:

• Utilized hepatocyte-specific ME1 knockout mice, overexpression models, and primary hepatocytes.
• Assessed liver injury, oxidative stress, mitochondrial function, ATP levels, autophagic flux, and ER stress.
• Employed biochemical, histological, molecular, and ultrastructural analyses, alongside pharmacological interventions.

Main Results:

• ME1 deficiency exacerbated AILI, characterized by increased lipid peroxidation, mitochondrial dysfunction, reduced ATP, impaired autophagy, and heightened ER stress.
• ME1 overexpression or reconstitution conferred protection against AILI, dependent on its catalytic activity.
• Malic acid demonstrated partial protective effects against APAP hepatotoxicity.

Conclusions:

• ME1 acts as a critical endogenous metabolic regulator in AILI.
• ME1 preserves hepatocyte survival by maintaining reductive capacity, bioenergetic balance, and adaptive stress responses.
• ME1's protective role is independent of altering APAP metabolic activation but linked to downstream metabolic pathways.