Related Experiment Video
Updated: Jul 1, 2025
Activating Autophagy by Aerobic Exercise in Mice
Published on: February 3, 2017
AIM2 regulates autophagy to mitigate oxidative stress in aged mice with acute liver injury
Chao Hu1, Mengjing Li1, Yongzhen Chen2
1Department of Geriatrics, Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
Abstract:
The cytoplasmic pattern recognition receptor, absent in melanoma 2 (AIM2), detects cytosolic DNA, activating the inflammasome and resulting in pro-inflammatory cytokine production and pyroptotic cell death. Recent research has illuminated AIM2's contributions to PANoptosis and host defense. However, the role of AIM2 in acetaminophen (APAP)-induced hepatoxicity remains enigmatic. In this study, we unveil AIM2's novel function as a negative regulator in the pathogenesis of APAP-induced liver damage in aged mice, independently of inflammasome activation. AIM2-deficient aged mice exhibited heightened lipid accumulation and hepatic triglycerides in comparison to their wild-type counterparts. Strikingly, AIM2 knockout mice subjected to APAP overdose demonstrated intensified liver injury, compromised mitochondrial stability, exacerbated glutathione depletion, diminished autophagy, and elevated levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Furthermore, our investigation revealed AIM2's mitochondrial localization; its overexpression in mouse hepatocytes amplified autophagy while dampening JNK phosphorylation. Notably, induction of autophagy through rapamycin administration mitigated serum alanine aminotransferase levels and reduced the necrotic liver area in AIM2-deficient aged mice following APAP overdose. Mechanistically, AIM2 deficiency exacerbated APAP-induced acute liver damage and inflammation in aged mice by intensifying oxidative stress and augmenting the phosphorylation of JNK and ERK. Given its regulatory role in autophagy and lipid peroxidation, AIM2 emerges as a promising therapeutic target for age-related acute liver damage treatment.
Insights
Absent in melanoma 2 (AIM2) negatively regulates acetaminophen-induced liver damage in aged mice. AIM2 deficiency worsens liver injury by increasing oxidative stress and lipid accumulation, highlighting AIM2 as a therapeutic target.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Absent in melanoma 2 (AIM2) is a cytoplasmic sensor for cytosolic DNA, known to activate inflammasomes and contribute to host defense.
- The role of AIM2 in acetaminophen (APAP)-induced liver injury, particularly in aged populations, is not well understood.
Purpose of the Study:
- To investigate the role of AIM2 in the pathogenesis of APAP-induced hepatotoxicity in aged mice.
- To elucidate the mechanisms by which AIM2 influences liver damage and identify potential therapeutic targets.
Main Methods:
- Comparison of APAP-induced liver injury in AIM2-deficient aged mice and wild-type controls.
- Assessment of liver injury markers, lipid accumulation, mitochondrial stability, glutathione levels, autophagy, and signaling pathways (JNK, ERK).
- In vitro studies involving AIM2 overexpression in hepatocytes and in vivo experiments with autophagy induction via rapamycin.
Main Results:
- AIM2 deficiency exacerbated APAP-induced liver injury, characterized by increased lipid accumulation, hepatic triglycerides, oxidative stress, and compromised mitochondrial stability.
- AIM2 knockout mice showed diminished autophagy, elevated JNK and ERK phosphorylation, and glutathione depletion.
- AIM2's mitochondrial localization was confirmed, and its overexpression enhanced autophagy and reduced JNK phosphorylation in hepatocytes.
- Rapamycin-induced autophagy mitigated liver injury in AIM2-deficient aged mice post-APAP overdose.
Conclusions:
- AIM2 acts as a negative regulator in APAP-induced liver damage in aged mice, independent of inflammasome activation.
- AIM2 deficiency exacerbates liver injury by intensifying oxidative stress and altering lipid metabolism and autophagy.
- AIM2 represents a potential therapeutic target for mitigating age-related acute liver injury.
