Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control

TL;DR

This study shows that TBK1 helps prevent liver disease progression by maintaining healthy mitochondria and lysosomes in liver cells.

Contribution

The study identifies TBK1 as a novel regulator of mitophagy and lysosomal activity in MASH progression.

Findings

TBK1 deficiency causes accumulation of damaged mitochondria and increased ROS production.

TBK1 modulates p62 phosphorylation and mTOR signaling to maintain lysosomal function.

Restoring TBK1 via AAV8 delivery reduces liver fibrosis and mitochondrial burden in MASH models.

Abstract

Mitochondrial dysfunction is a critical driver of metabolic dysfunction–associated steatotic liver disease (MASLD) progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here, we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1 knockout (LTKO) mice, we show that TBK1 loss leads to the accumulation of depolarized, ROS-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal acidification. Therapeutic restoration of TBK1 expression via AAV8 delivery enhanced mitophagy, reduced mitochondrial burden, and ameliorated liver fibrosis. Notably, both human samples and murine steatohepatitis models exhibited a significant decline in TBK1 kinase activity. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.

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