TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control

Area of Science:

• Hepatology
• Cellular Biology
• Biochemistry

Background:

• Mitochondrial dysfunction drives metabolic dysfunction-associated steatotic liver disease (MASH) progression.
• Mechanisms of hepatic mitochondrial quality control in MASH are not fully understood.

Purpose of the Study:

• To identify key regulators of hepatic mitophagy and lysosomal activity in MASH.
• To investigate the role of TANK-binding kinase 1 (TBK1) in liver homeostasis.

Main Methods:

• Utilized TBK1-deficient hepatocytes and liver-specific TBK1-knockout mice.
• Assessed mitophagy flux, lysosomal degradation, and mitochondrial function.
• Analyzed human samples and murine MASH models for TBK1 activity.
• Employed adeno-associated virus 8 (AAV8) for TBK1 restoration in MASH mice.

Main Results:

• TBK1 deficiency impairs mitophagy and lysosomal degradation, leading to mitochondrial accumulation and oxidative stress.
• TBK1 is crucial for p62 phosphorylation and modulates mTOR signaling, preserving lysosomal function.
• TBK1 kinase activity is significantly reduced in human and murine steatohepatitis.
• TBK1 restoration in MASH mice enhanced mitophagy, reduced mitochondrial burden, and ameliorated liver fibrosis.

Conclusions:

• TBK1 is an essential regulator of hepatic mitophagy and lysosomal homeostasis.
• Declined TBK1 activity contributes to MASH pathogenesis.
• TBK1 represents a potential therapeutic target for MASH.